Briash Mtdical BulUlm (1992) Vol. 48, No. 2, pp. 276-308 © The Britilh Coimcil 1992

Hormone replacement therapy and cardiovascular disease T W Meade A Berra MRC Epidemiology and Medical Care Unit, Northviick Park Hospital, Harrow, UK

Oestrogen alone probably confers a degree of protection against ischaemic heart disease and stroke and is appropriate for women requiring hormone replacement therapy (HRT) who have undergone hysterectomy. However, the cardiovascular effects of the progestogens used with oestrogen in the much larger number of women who have not undergone hysterectomy are unknown. Some widely used progestogens have adverse effects on lipoprotein levels and may raise blood pressure. The antithrombin III level may be involved in determining the response to oestrogen in different settings. The indications for HRT and the effects of different formulations on cardiovascular disease constitute one of the most pressing but complex issues in present-day medical practice. These questions can only be satisfactorily answered by the randomised controlled trials that should have been initiated several years ago and the feasibility of which is only now being investigated.

It is not difficult to summarise the main conclusion to be drawn from currently available evidence on hormone replacement therapy (HRT) and cardiovascular disease. This is that oestrogen alone, unopposed by a progestogen, probably confers worthwhile protection against ischaemic heart disease (IHD) and also, though less certainly, against stroke. However, this evidence is a guide to only a fairly small proportion of current clinical practice involving HRT and is inadequate—perhaps even misleading—for what is

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one of the most pressing but complex issues in present-day medical practice. To understand the contemporary situation and its challenges, it is useful first to summarise developments that have influenced views and opinions about HRT. Oestrogen replacement treatment for menopausal symptoms and post-menopausal bone loss gradually became more frequent over the period during which the risk of thromboembohsm due to oral contraceptives (OC) was increasingly appreciated. At that time, the explanation for the apparent effect of OC on thromboembolism was considered almost exclusively in terms of the oestrogen in OC. It was therefore widely assumed that oestrogen used as HRT would have the same effect. Indeed, in the light of present knowledge it is ironic that this concern was a major reason, on ethical grounds, against randomised controlled trials (RCTs) of HRT at the time when these should certainly have been initiated. With the growing use of HRT in clinical practice, two particularly significant observations were made. One was the undoubted increase in the incidence of uterine cancer attributable to unopposed, i.e. oestrogen only, HRT. While the relative risk of uterine cancer due to unopposed HRT is appreciable, its incidence is relatively low so that the absolute risk of uterine cancer due to HRT is fairly small. Furthermore, the tumour generally has a good prognosis. Understandably, however, the use of HRT declined following the demonstration of the relationship. The second development was the publication of early studies on HRT and cardiovascular disease tending to show that oestrogen alone seemed not to increase the risk of IHD but actually to confer a degree of protection against it. To prevent the risk of uterine cancer associated with unopposed oestrogen, women who had not had a hysterectomy were increasingly prescribed opposed oestrogen, the most widely adopted procedure being the inclusion of progestogen during the last ten or twelve days of each cycle. However, while this modification has been successful in virtually removing the increased risk of uterine cancer, further work on the effects of OC had by then clearly showed that two of the progestogens often used in combined OC preparations (norethisterone acetate and norgestrel) also contributed to the increased risk of thromboembolism.1'2 Metabolic studies demonstrated that some progestogens in OC have what would be regarded as adverse effects on lipoprotein levels3 and that they may also lead to an increase in blood pressure. 45 Although direct analogies between OC and HRT should only be drawn with

278

HORMONE REPLACEMENT THERAPY

caution, it was nevertheless understandable that despite the beneficial effect of progestogen on uterine cancer incidence, there was then concern that opposed regimes might increase the risk of cardiovascular events. For some women, bleeding and the occurrence of pre-menstrual symptoms with opposed HRT is another potential drawback of these regimes which, though obviously less serious than major cardiovascular episodes, should still not be overlooked, as treatment may need to be continued for many years. In a particularly controversial field, and bearing in mind that degenerative arterial disease is the leading cause of death and serious illness in post-menopausal women, one point on which nearly all now agree is the importance of trying to establish the cardiovascular effects of opposed HRT. However, this is not a simple proposition. There are currently numerous formulations of HRT available. They contain different oestrogens and different progestogens, singly or in combination. New preparations and methods of delivery are under active study and development, often with precisely the objective of reducing any cardiovascular risk. To speak simply of opposed and unopposed preparations is therefore a considerable oversimplification. Currently, Premarin is probably the most widely used unopposed preparation in the United Kingdom and Prempak-C the most widely used opposed preparation. It is therefore useful to refer to them for illustrative purposes, particularly Prempak-C. First, there is the obvious question of progestogen dose. There are 75 ug 1-norgestrel in each of the 12 tablets at the end of a cycle pack of Prempak-C, less than the 150 ug in the oral contraceptive Microgynon-30, for example. Another preparation, Cyclo-Progynova, contains 250 ug 1-norgestrel (with oestradiol valerate). In Menophase, the highest dose of norethisterone is 1.5 mg, the same as or slightly more than several OC formulations in current use. Secondly, the progestogen in HRT is taken intermittently rather than continuously (as in many OC preparations), a possibly reassuring consideration. At the same time, HRT users may be more or less responsive than OC users to any adverse effects of progestogens. Metabolic changes due to progestogens (summarised in a later section) do to some extent replace these theoretical considerations with surrogate indices. But while these may suggest that there is some cause for concern—particularly the presumably adverse effects on blood lipids—they are not a substitute for the clinical events of principal concern, myocardial infarction (MI) and stroke. So nothing can be taken for granted. Opposed HRT may have the same (i.e.

HRT AND CARDIOVASCULAR DISEASE

279

protective) effect against cardiovascular disease as unopposed treatment or it may reduce, abolish or even reverse this effect. Clearly, a key feature in considering these possibilities and their implications is the degree of protection conferred by unopposed HRT. This is considered in later sections. A figure often quoted is a 50% reduction in the incidence of IHD compared with women not taking HRT. So far, however, this estimate (which may in any case not be entirely justified) is based on observational as distinct from experimental studies (i.e. randomized controlled trials). Observational studies compare the outcome in patients taking HRT in the ordinary course of medical practice with the findings in women not on treatment. However, the decision to use HRT may have been influenced by considerations related to the risk of developing cardiovascular disease. Indeed, this would not be surprising given that many of the women in the studies in question started HRT at a time when, as it has already been pointed out, it was often assumed that HRT would if anything increase the risk of IHD and stroke. Consequently, it is by no means impossible that women taking HRT in the early observational studies were at an intrinsically lower risk of these events than those not doing so. This possibility can be allowed for to some extent by correcting for differences between HRT takers and non-takers that are likely to affect the results. There is, however, one good example for which the results of both observational and experimental studies are available—the value of oral anticoagulants after myocardial infarction (MI). In the early observational studies of these agents, it seemed possible that those with a better prognosis anyway (e.g. without evidence of heart failure) tended to be selected for treatment more often than those with a poorer prognosis.6 The apparent value of oral anticoagulants was thus probably overestimated since the patients who received this treatment were likely to fare relatively well anyway. Fortunately, several RCTs were also carried out on oral anticoagulants after MI. These and the observational studies have been considered in an interesting review7 which contrasted the 20% benefit in the trials with the 50% benefit from observational studies, the latter figure being very similar to the estimate already referred to for unopposed HRT. What is the reason for the substantial difference between the estimated benefit from observational and experimental (i.e. RCT) studies of anticoagulants? Probably the most likely explanation is the inability of observational studies fully to allow for confounding characteristics, either because those that have

280

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been considered have been measured too imprecisely or because others that have not been measured, or perhaps not even identified, have not been taken into account at all. The possibility8 and, in the UK, the likelihood9 that HRT users are at intrinsically lower risk of IHD have both recently been alluded to. Moreover, the apparent benefits of HRT may not be specific for IHD, also suggesting that it is perhaps the general health characteristics of HRT users, rather than HRT itself, that explain their relatively favourable experience. To suggest, therefore, that a 50% reduction in major cardiovascular events due to unopposed HRT may be a considerable overestimate is not just a theoretical consideration. It probably is true that unopposed HRT confers a degree of protection but: (a) this may be a good deal less than is still often assumed; and (b) it is in any case the unknown effects of opposed HRT in the majority of women who have not undergone hysterectomy that is of greatest relevance. HRT AND CLINICAL MANIFESTATIONS OF ARTERIAL DISEASE Before reviewing individual studies and summarising their findings, it is worth re-emphasising some of the features which may limit their contemporary value. First, the very large majority have been carried out in the USA, frequently in somewhat unusual populations. Secondly, they have been based on preparations used at the time and not necessarily relevant to current practice, an obvious but important consideration. Most concern the use of unopposed oestrogen in the form of Premarin, conjugated equine oestrogens. Thirdly, the statistical power of the studies reviewed depends mainly on the number of events, rather than the size of the initial study population. Finally, some tendency to select those at low risk of arterial disease for HRT is almost certain and the analytical difficulties of fully allowing for this have already been considered. Some other points about the way in which the relevant studies have been summarized should be also noted. The purpose of Tables 1 and 3 is to give only the salient characteristics and main findings of each study, which are presented in the order in which patients were recruited. In the case-control studies (Table 1), the relevant HRT preparations will have been those used a variable number of years previously while for the prospective studies (Table 3), the preparations will have been those current during the recruitment periods shown. A variety of methods have been used for collecting details of morbidity, mortality and

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281

HRT use—for example, posted questionnaires and patient interviews. Some studies have been concerned only with fatal events and some have given details about both fatal and non-fatal events, while others have dealt with the sum of fatal and non-fatal events without distinguishing between the two. The original publications should be consulted for these details in particular studies. Here, unless otherwise stated, IHD refers to major episodes, MI and/ or coronary death, however these were defined. CVA refers to stroke other than subarachnoid haemorrhage. The relative risks (RR) shown are for those using HRT compared with those not and Tables 1-3 show RRs adjusted for confounding characteristics in preference to unadjusted values. For consistency, relative risks have been rounded to one decimal place. Use can be considered as current, past or ever-use, i.e. current and past users combined. Again, the original publications should be consulted for definitions in particular studies. In general, Tables 1-3 are based on everuse, with comments in some cases where there appear to have been interesting and potentially important differences, e.g. lower RRs in current dian past users, suggesting that discontinuation of HRT may have reduced a protective effect. These considerations account for some generally minor differences between this and other reviews. A more substantial difference, however, arises over the results of the Walnut Creek study.10 Other reviews11'12 have used data from earlier publications and in one case11 gave results for fatal acute MI only (RR 0.5), whereas this review shows the RR of 1.3 for all IHD, which seems more appropriate. Finally, there is the particularly difficult question of attempting an overview of the results of separate studies in order to suggest overall estimates. This has recently been undertaken by Stampfer and Colditz13, who acknowledge the methodological difficulties. Here, the point estimate for the RR in each study has been taken at its face value with the exception of the case-control study by Jick et al.14 in Table 1, which has been omitted. This method gives the same weight to the particularly unsatisfactory early prospective studies, which suggested large benefits due to HRT, as it does to later and less unsatisfactory studies suggesting no effect or an adverse influence of HRT (or a beneficial effect). It will be seen that this approach suggests a protective effect of HRT against IHD and stroke which is not, however, as substantial as the figure of 50% already referred to and which may, after taking account of confounding effects that have not been fully allowed for, be quite marginal. Once again, this emphasises the importance of evidence from RCTs, if possible.

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HORMONE REPLACEMENT THERAPY

Other reviews have adopted the useful convention of presenting the findings for case-control and prospective studies separately, and this is followed here. It is interesting that the authors of several of the earlier studies comment on their findings in terms of the absence of a harmful effect rather than the confirmation of benefit, reflecting the expectations that led to the initiation of these studies. Case-control studies The results of these studies are summarised in Table 1. Beard et al.15 included 18 sudden unexpected deaths likely to be due to IHD, 90 cases of MI (and 133 of angina) among female residents in Rochester, Minnesota aged 40 to 59 during the years 1960-1982. Two community controls were selected for each case. The RR for the association of IHD with 'steroidal oestrogen use' was 0.6, though not statistically significant (for angina, the RR was 0.8.). In 1976, Pfeffer and van der Noort 16 found no significant association between oestrogen use and stroke in a comparison of 210 stroke patients and 1034 matched controls in a retirement community. A possible association between oestrogen use and nonembolic cerebral infarction in those aged 70-79 may have been secondary to an interaction between hypertension and oestrogen usage. Pfeffer et al.17 also studied some 15 500 women over an 11 year period during which 220 women experienced myocardial infarction (MI). The relative risk (RR) of MI associated with HRT was 0.7 for current usage and 0.9 for ever usage, the confidence intervals for both estimates including 1.0. There was, therefore, no conclusive evidence of a relationship between oestrogen use and MI. The authors suggested the already high coronary risk in their study population, the low oestrogen dose and the short duration of treatment as possible explanations for the apparent absence of an association. In a nested case-control study within the large prospective study by the Royal College of General Practitioners18 and primarily concerned with the effects of oral contraceptives, die RR of acute MI associated with HRT was 0.8. (This study could also appropriately be considered in Table 3.) In 1976, Rosenberg et al.19 reported on 336 MI patients and 6730 'reference patients' and found that 2.4% (8 women) and

Table 1 Summary of case-control studies Authors

Country

Beard et al.

15

Recruitment

Population

USA

1960-82

Age at entry

HRT

40-59

CEE

Pfeffer and van der Noort.16 Pfeffer et al.17

USA

1964-73

USA

1964-74

18 Croft and Hannaford. Rosenberg et al.19 Szklo et al.20 Ross et al."

UK USA USA USA

1968-69 1969-72 1971-72 1971-75

USA

1975

Residents of Rochester, Minnesota Californian retirement community Californian retirement community General practice Hospital patients Hospital patients Californian retirement community Hospital patients

Bain et al.21 Rosenberg et al.23

USA USA

1976 1976-77

Nurses Hospital patients

30-55 30-49

Adam et al.2*

UK

1978

50-59

UK

1982-86

Deaths in England and Wales General practice

Jicketal.

14

Thompson et al.

25

"see text for current use 'HRT users among 158 CIKI of myocardial infliction, stt ton rd»o *0.7 for current uie •Oestrogen only, opposed treatment and progestogen only, in Table 2 IHD: Ischaemlc hemrt disease CVA: Stroke SAH. Sub-ertchnoid haemorrhage CVD: Cardiovascular disease (IHD and CVA) CEE: conjugated equine oestrogen! O: oestrogen alone (asiumed or stated) HRT: type not specified

No. cases

Relative risk" 0.6

58-98

IHD: 86 (mainly) ?CEE CVA: 210

57-98

?CEE

IHD: 220

0.9b

20->60 40-75 35-64 73 (median)

HRT CEE O

IHD: 9° IHD: 336 IHD: 39 IHD: 146

0.8 1.0 0.6 0.4

39-45

CEE

IHD: 17 (mainly) ?CEE IHD: 123 ?CEE IHD: 477 (mainly) HRT IHD: 76 SAH:23 3 types" CVD:603

7.5

45-69

?CEE (mainly)

1.1

0.9^ 1.0 0.7 0.6 1.3

O GO

n

en W

to 00

284

HORMONE REPLACEMENT THERAPY

4.9% (330 women) respectively were regular oestrogen users at or shortly before the time of hospitalisation, giving an RR of 0.5. However, after allowing for age, past history, angina, diabetes, hypertension and cigarette smoking the summary point estimate was 1.0. Szklo et al.20 studied 39 matched sets (33 pairs and 6 triplets) of post-menopausal white women experiencing MI and control patients. The unadjusted RR for past oestrogen use was 0.8. Allowance for cardiovascular diseases, smoking, education and type of menopause, however, resulted in an RR of 0.6. Any protective effect was seen mainly in those who had undergone a surgical menopause, in whom the RR was 0.4. None of these results was statistically significant but the similarity of the finding in those who had undergone a surgical menopause with the finding in those who had had bilateral oophorectomy in the study by Bain et al.21 may be of some interest. It was probably the study by Ross et al. in 198122 that chiefly marked the change from considering HRT as likely to cause arterial disease to the view that it might well be protective. This study (and others from the same group) was carried out among the residents of a retirement community near Los Angeles. As the report says, the residents are 'almost uniformly white, highly educated andfinanciallywell to do' and not necessarily, therefore, very representative of any population as a whole. From 1971, death certificates of all those who died while in the community were analysed and this study was based on 146 patients aged 73, on average, who died between 1971 and 1975. Controls were selected by search of the 1976 register of residents and a second control was selected from those who had died during the study period, excluding those whose cause of death was possibly related to oestrogen, i.e. cancer of the breast, ovary or endometrium, fracture-related conditions, cerebrovascular disease and other arterial diseases. The RR for death from IHD associated with the use of conjugated oestrogens was 0.4, with a 95% confidence interval of 0.2-0.8, i.e. statistically significant. The association did not appear to be due to identifiable confounding factors. Surprisingly, categorization of those who had had IHD was not made 'blind' of information about HRT usage. The outstanding exception to the other case-control studies, which have suggested either no effect of HRT or a degree of protection, is that of Jick et al.14 who reported an RR for MI of 7.5, with a 90% confidence interval of 2.4-24. However, the study

HRT AND CARDIOVASCULAR DISEASE

285

was based on only 17 MI cases all but one of whom were cigarette smokers, and on only 34 control subjects 18 of whom were ex- or non-smokers. Bain et al.21 collected information by postal survey about MI, use of female hormones after the menopause and about coronary risk factors from 121 964 registered nurses aged 30-55. Of these, 123 were hospitalised for MI during the study period. Compared with non-users, the RR for women who had ever taken female hormones was 0.9 while for current use is was 0.7. Again, both confidence intervals included 1.0 so the results were not statistically significant. An additional observation, however, was the RR of 0.4 in current users who had had both ovaries removed, which was statistically significant. In this group, the RR for ever users was 0.6. While it would be wrong to make too much of the relatively small difference between current and ever use in this particular group, it is nevertheless what might be expected on discontinuation of any effective treatment in a high risk group. In 1980, Rosenberg et al.23 reported on 477 women aged 30 to 49 experiencing a first MI and on 1832 hospital controls. The RR of acute MI for those who had used non-contraceptive oestrogens in the preceding month was 1.0, or 1.2 for those who had discontinued oestrogen more than a month previously. In a pilot case-control study, Adam et al.24 compared 76 cases of MI with 151 controls. The RR of MI was 0.7. Only about 3% of the 45-69 year old women were using HRT at any given time during the study year. These authors also included 23 cases of subarachnoid haemorrhage, compared with a further 45 controls. The RR was 0.6. The largest number of cases was included in the study carried out by Thompson et al.25 through the Medical Research Council's General Practice Research Framework. This study was concerned with both MI and stroke, the results being presented for both conditions combined (CVD, cardiovascular disease) since there was no evidence of different relationships of the two conditions with HRT. A total of 603 events (359 MI, 244 strokes) was reported from 83 general practices throughout England, Scotland and Wales in women aged 45-69, for each of whom two controls were selected. As with the other British study, the prevalence of current use of HRT was low, at only 1%, though 14% of controls and 18% of cases had received more than one HRT prescription in the past. An important design feature was the distinction between different types of HRT, preparations containing oestrogen

286

HORMONE REPLACEMENT THERAPY

alone, progestogens alone and combined oestrogen-progestogen regimes being evaluated. The results of the study are summarised in Table 2. While they provide no evidence that the use of HRT as recently prescribed in the UK constituted a major cardiovascular risk, they did not suggest any degree of protection, either. At face value, i.e. without weighting individual studies according to their relative contribution and omitting the study by Jick et al.,14 the results as a whole suggest a reduction of about 25% in the risk of IHD attributable to the use of HRT and of little or no effect on stroke. Prospective studies The results of these studies are summarised in Table 3. Burch et al.26 studied 737 hysterectomised women observed for a total of 9869 patient years. The source of expected events is unclear but appears to have been general population mortality rates. There were 9 deaths from heart disease compared with 21 expected. For stroke, there were 8 observed and 9 expected deaths. The results must be interpreted extremely cautiously. Hammond et al.27 studied 610 'hypoestrogenic' women, each for at least 5 years. The commonest diagnosis was 'menopausal syndrome' followed by atrophic vaginitis, bilateral oophorectomy, premature ovarian failure, osteoporosis and other conditions. Oestrogen was used in 301 patients but not in the remaining 309. Those treated with oestrogen were younger, weighed less, had lower blood pressure and were more likely to be white, private patients with fewer pregnancies than the untreated group. The authors themselves draw attention to these differences, for which only limited allowance was made. Consequently, the low relative risks of about 0.3 for IHD and 0.2 for stroke have to be interpreted especially cautiously. The main results of the Walnut Creek Contraceptive Drug Table 2 Relative risks (RR) of major cardiovascular disease (MI or stroke) in UK case-control study in general practice, adjusted for marital status, smoking and family and past medical history2* Any HRT Oestrogen only Oestrogen and progestogen Progestogen only

1.3 1.1 1.2 1.0

N.B. 'Any HRT* ii not i simple iverage of those on particular regimes, between which the confounding variables also differed. None of the RRs is stansticaUy significant.

Table 3 Summary of prospective (cohort) studies Authors Burch et al.

26

Hammond et al.

27

Petitti et al.10 Wilson et al.

29

Country

Recruitment

USA

1940-67

USA USA

Age at entry

HRT

No. cases

737 hysterectomy patients

25->85

CEE

1940-69

610 hypoestrogenic patients

50

O

0.4 0.9 0.3 0.2

1968-72

6093 women in pre-paid health scheme 1234 women in Framingham community

18-54

o

IHD: 9 CVA: 8 IHD: 58 CVA: 17 IHD: 21 CVA: 9 IHD: 116 CVA: 45

2269 women in screening for L R C trial 1868 women in Californian community 48 470 nurses

40-69

CVD: 55

0.4

IHD: 87 CVD: 147 IHD: 405 CVA: 224 IHD: 36 CVA: 23

1.0 1.0

0.6\ l.OJ 0.4 0.5

p

IHD: 149

0.6

2 o

CVA: 63

0.5

n

USA

1970-72

Bush et al.30

USA

1971-76

Criqui et al.31

USA

1972-?

Stampfer ct al.32

USA

1976-78

Hunt et al. 3334

UK 3

Population

1978-82 (mainly)

Henderson et al. '

USA

1981-85

Paganini-Hill et al.3*

USA

1981-85

4544 women in specialist menopause clinics 8841 women retirement 8807 women retirement

in Californian community in Californian community

>50

CEE (almost all) CEE (mainly)

50-79

O

30-63

CEE in

45-54 (mainly) 73 (median) 73 (median)

72% 43%

'opposed' usage CEE (mainly) CEE (mainly)

Relative risk'

1.3" 0.6 1.9 2.3

X pa

o

h

"see text

*RR 0.3 for acute MI TJpld Research Clinics 'current use IHD: Ischaemk heart disease CVA: Stroke SAH: Sub-arachnoid haemorrhage CVD: Cardiovascular disease (IHD and CVA) CEE: conjugated equine oestrogens O: oestrogen alone (assumed or stated) HRT: type not specified

to

00 -0

288

HORMONE REPLACEMENT THERAPY

Study10 come from a 10-13 year follow-up of mortality in 3437 women who never used oestrogens or OC and 2656 women who used oestrogens but not OC. (When it initially reported,28 relative risks were close to 1.0 perhaps because study participants were still young and had not been exposed to non-OC oestrogen for very long.) Mortality from all causes of death was 1.64 per 1000 woman years in oestrogen users compared with 2.06 per 1000 woman years in non-users. Part of the explanation for the apparently more favourable experience of the oestrogen users was lower mortality from accidents, suicide and homicide, an observation that might have reflected differences in life-style between users and non-users or that might have been due to the beneficial effects of oestrogen on mental state. The relative risk of death from acute MI in users was 0.3 but for all IHD, it was 1.3. The relative risk to users of death from cerebrovascular disease was 0.6. None of these associations was statistically significant. For all IHD, the numbers of deaths were 12 and 9 in non-users and users respectively—not large (emphasising the considerable problems faced in studies of IHD in women) but larger than the numbers on which deaths from acute MI (7 and 4, respectively) and all cerebrovascular disease (4 and 5, respectively) were based. It is the study by Wilson et al.29 that has provided the greatest cause for comment. The work was based on the Framingham Heart Study twelfth biennial examination as the entry or index examination. Medication recorded at that and the previous 4 biennial examinations was used 'to classify the degree of oestrogen exposure' before 8 years of observation for cardiovascular morbidity and mortality. Even though the women reporting postmenopausal oestrogen use at one or more of the relevant examinations appeared to be at intrinsically lower risk of cardiovascular disease than those who did not, they experienced nearly twice the incidence of IHD and more than a two-fold risk of stroke subsequently, compared with the non-users. It was particularly in users who also smoked that the excess risk of MI was observed. Several criticisms of the study have been made. For example, oestrogen usage during the follow-up period was not described, which is not unique to this study. However, those who have commented on potential shortcomings have also agreed that the findings cannot simply be dismissed out of hand (particularly—it should be added—in view of the shortcomings in some of the other cohort studies that have reported apparently protective effects).

HRT AND CARDIOVASCULAR DISEASE

289

Bush et al.30 studied mortality among 2269 white women aged between 40 and 69 who had been followed-up for an average of 5.6 years in the Lipid Research Clinics Program Follow-up Study. There were 72 deaths, the lower relative risk of death in oestrogen users varying according to the extent of previous gynaecological surgery, i.e. 0.5 in those who had not had a hysterectomy or oophorectomy, 0.3 in those who had undergone hysterectomy and 0.1 in those who had had both ovaries removed. When the 17 deaths due to breast, ovarian or uterine cancer were omitted, the relative risk of death in users compared with non-users was 0.4, with confidence limits of 0.2 to 0.9, i.e. statistically significant and providing an estimate of the protective effect of oestrogen against death from cardiovascular disease, since this is likely to have been the main cause after the exclusions. Some of the lower risk of mortality in oestrogen users could be accounted for by increased levels of high-density lipoprotein cholesterol. To illustrate the difficulties of interpretation in non-randomised studies, the authors point out that while there were no significant differences for any single class of other medication, more of the oestrogen users were taking antihypertensive agents, anti-anginal agents, diuretics or anti-arrhydimics. This might mean that the users were at intrinsically greater risk of cardiovascular disease than the non-users, in which case the protective effect of oestrogen may have been under-estimated. On the other hand, it may have been the cumulative effects of these other agents (for which analytical allowance was apparently not made) that partly contributed to the better survival in the user group. Criqui et al.31 studied 1868 women aged between 50 and 79 living in a 'planned community' in California. Recruitment began in 1972. After 12 years and adjusting for age and a range of potentially confounding characteristics, mortality from all causes was about 20% lower in those who had used post-menopausal oestrogen, an effect that was not quite statistically significant at a conventional level. There were complex interactions between oestrogen use and smoking. In both those who had never smoked and in current smokers, the reduction in mortality from all causes appeared to be more than 30% and was statistically significant. Ex-smokers, however, did not appear to be protected by postmenopausal oestrogen use. These effects on all causes of mortality were generally reflected in the findings on mortality from cardiovascular disease and IHD. Post-menopausal oestrogen use seemed to reduce IHD mortality very substantially in current smokers,

290

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had little effect in those who had never smoked and more than doubled the relative risk in ex-smokers. For all women, the RR of IHD associated with HRT was 1.0. In a further analysis of mortality over three years in those still alive after the first 9 years of the study, reduced death rates were seen only in women using oestrogen both at entry to the study and 9 years later. The authors suggest that the apparently large reduction in post-menopausal oestrogen use during the study period may therefore have resulted in an under-estimate of the true value of continued use. On the other hand, the findings according to smoking habit—with benefit in current smokers and an adverse influence in ex-smokers—are puzzling. This study provides a good example of possible selection effects, HRT users being significantly younger than non-users and being at significantly less risk of IHD on the grounds of cholesterol, blood pressure, blood sugar, body mass and social class, but at greater risk on account of smoking. Stampfer et al.32 surveyed 121 700 female nurses aged between 30 and 63 by postal questionnaire. They accumulated 337 854 person-years of observation among 48 470 post-menopausal women of whom 405 had major episodes of IHD and 224 had strokes, subsequently. In current HRT users, the relative risk of major IHD, adjusted for age and other risk factors, was just under 0.6 with 95% confidence limits of 0.4-0.8, i.e. significant. For former users, the adjusted relative risk was 0.8 (non-significant), the greater protection in current than former users strengthening the case for a protective effect. In women who had undergone a natural menopause, the relative risk of major IHD in current users was 0.6 while in those who had undergone bilateral oophorectomy it was 0.4. For stroke, the adjusted relative risk was nearly 1.0, i.e. no protective effect. Most of the HRT in this study was with oral conjugated oestrogens. The proportions of all the HRT that was with other formulations were too small for separate analyses. Hunt et al.33 have been studying 4544 long term users of HRT whose mortality is compared with expected rates in the female population of England and Wales. As the authors themselves point out, their study population is highly selected and the use of national rates for comparative purposes is not ideal. In their first report, there were 20 deaths from IHD and the relative risk in those who had used HRT was 0.5, with 95% confidence limits of 0.3-0.7, i.e. statistically significant. While Premarin remained the most commonly used preparation, substantial use of opposed regimes was also recorded. The relative risk of cerebrovascular

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291

disease was 0.7 and for all circulatory disease it was 0.5. In the second report by Hunt et al.,34 based on mortality to the end of December 1988, the relative risks in HRT users of IHD, cerebrovascular disease and all circulatory disease were 0.4, 0.5 and 0.4 respectively, all statistically significant. Updated information comparing opposed and unopposed regimes was not available. The chief value of this study may be in detecting changes in risk with increasing exposure to HRT (for example, in breast cancer) rather than in accurately estimating risks relative to those in non-users. Henderson et al.35 conducted their study through the same Californian retirement community previously referred to in the section on case-control studies. They enrolled 8841 women aged between 44 and 101 years. By 1987, there had been 1019 deaths. Those who had used oestrogen replacement therapy had a relative risk of death from all causes of 0.8 compared with those who had never used it. The benefit was largely due to the reduction in mortality from acute MI, the relative risk in users being 0.6 and statistically significant. In addition to the findings on mortality, the relative risk of hospitalisation for acute MI was also lower in users than non-users. Again in the Californian retirement community, Paganini-Hill et al.36 compared mortality from stroke in those who did or did not receive HRT. Of 4962 women who used HRT, 20 died from stroke compared with 43 out of 3845 who did not, giving a relative risk of 0.5, 95% confidence interval 0.3-0.9 (i.e. significant). Finally, a small, double-blind randomised comparison in 84 pairs of post-menopausal in-patients (not shown in Table 3)37 compared high dose conjugated oestrogens and progesterone with placebo treatment over a 10 year period. Active treatment led to what would be regarded as beneficial changes in lipoprotein patterns. MI occurred in 1.2% of those on active treatment compared with 3.7% of the controls but the numbers were clearly far too small to place any weight on the finding, as the authors themselves recognised. At face value, and including the relative risk of 1.9 from the Framingham study,28 a summary of the studies considered here suggests an incidence of IHD about 20% lower and of stroke about 15% lower in HRT users than non-users. The figure of 20% for IHD contrasts with an estimate of about 45% from the analysis by Stampfer and Colditz,13 who did allow for the statistical power of different studies, as far as possible. They also included some other small, clinical studies tending to give very low relative

292

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risks, i.e. favourable to HRT, and the results of angiographic studies which also gave low figures, but whose interpretation is open to question (see below). Whether dose and duration of HRT treatment affect the outcome are questions of obvious importance. In summary, findings are largely inconclusive.12 More suggestive of a truly beneficial effect, however, is the tendency towards a gradient of lower relative risks from never to past and then current users of HRT. 11

PATHOLOGICAL AND METABOLIC EFFECTS OF HRT Particularly in view of the difficulties of establishing the relationship between HRT and clinically manifest arterial disease, it is necessary to consider the structural, functional and metabolic pathways through which HRT may influence the incidence of cardiovascular disease. For several reasons, however, these intermediate or surrogate measures are no substitute for the clinical events (myocardial infarction, coronary death and stroke) of primary concern. First, while atheroma is a necessary precondition, it is plaque fissuring and the superimposed thrombus that are the more proximate causes of the clinical event. For a given extent of atheroma, it seems increasingly likely that the coagulability of the circulating blood plays a leading part in whether or not thrombosis occurs. Consequently, any relationship between HRT and atheroma— though certainly interesting—can provide only a partial explanation for clinical as distinct from pathological manifestations. Secondly, pharmacological agents often have several effects, some of which may suggest benefits, others hazards. For example, while diuretics and [^-blocking agents both lower blood pressure, they often have adverse effects on lipoproteins.38 This observation may be relevant to the contrast between the undoubted benefit due to the diuretic bendrofluazide against stroke, where raised blood pressure but not so obviously high cholesterol levels are involved, by comparison with its apparent lack of effect against IHD, 39 where high cholesterol levels clearly are important. Furthermore, pharmacological agents may exert dieir beneficial effects through unidentified pathways, bendrofluazide again providing a good example,40 or through pathways not originally considered significant, the possibility that clofibrate operates at least as much through its effects on fibrinogen as on cholesterol being an example in this case.41 Thus, findings based on surrogate measures must be

HRT AND CARDIOVASCULAR DISEASE

293

considered with reservation and as only part of the evidence as a whole. Mechanisms through which HRT may influence the risk of arterial disease and which have been studied include the pathological changes of atheroma, effects on lipid metabolism, on blood pressure, on haemostatic variables and effects on vessel function. The pathological studies considered below were large, well planned and consistent in their findings. The general indications of the larger studies on lipid metabolism are also fairly consistent in their results as are those on some of the haemostatic effects of HRT. By contrast, many of the numerous studies on HRT and blood pressure have been small, often poorly designed and in many respects inconsistent in their results. Finally, only limited work has so far been carried out on the effects of HRT on vascular tone and blood flow. Pathological studies Studies relating post-menopausal use of oestrogen to changes in the coronary arteries at angiography suggest substantial benefit. Gruchow et al.42 studied 993 women aged between 50 and 75 undergoing angiography, of whom 154 were oestrogen users and 779 were non-users. Users had lower occlusion scores than nonusers. The age-adjusted odds ratios for use of post-menopausal oestrogen among those with moderate or severe levels of occlusion in the coronary arteries were 0.6 and 0.4 respectively, both statistically significant and suggesting a protective effect of postmenopausal oestrogen on coronary occlusion. Other analyses suggested that high high-density lipoprotein cholesterol (HDL) levels among the users might be a biological mechanism by which oestrogen confers its benefit. Sullivan et al.43 studied 2188 patients undergoing coronary arteriography between 1972 and 1984. The odds ratio estimate of the risk of coronary artery disease for oestrogen users relative to that of non-users was 0.4 after adjustment for age, cigarette smoking, diabetes, cholesterol level and hypertension and was statistically significant. McFarland et al.44 reported a relative risk of 0.5, based on a comparison of 208 patients with no stenosis and 137 with 70% or more occlusion. Though highly suggestive of a protective effect, the results of these three studies do call for cautious interpretation. First of all,

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there may have been a degree of selection over those referred for angiography that could have been partly determined by perceived risk of coronary artery disease and/or oestrogen usage. Indeed, an interesting study in men comparing prospective with case-control methods for assessing characteristics associated with angiographic findings did suggest that the case-control approach may introduce biases sufficiently serious to give misleading results,45 on the assumption that the prospective approach is less prone to such biases. Secondly, the earlier years of recruitment to the studies were those when oestrogen treatment may well have been considered to increase rather than decrease the risk of coronary disease. Those considered to be at specially high risk might, therefore, have been prescribed HRT less frequently than those considered to be at lower risk. The studies made extensive adjustments to allow for this and other possibilities but, for reasons considered earlier, these adjustments may not always be adequate.

Lipid metabolism Since (as with clinical events themselves), much of the work on HRT and lipid metabolism is based on treatment with oestrogen onjy3,46.47 j t j s n e c e s s a r y a i s 0 t o consider evidence from studies on the effects of oestrogen and progestogen in OC users48'49 as well as the limited evidence there is from studies on opposed HRT. There is reasonable consistency in the results of these studies, suggesting that oestrogen lowers total cholesterol and low density lipoprotein (LDL) cholesterol and that it raises high density lipoprotein (HDL) cholesterol, while some progestogens have adverse effects on lipoprotein metabolism. Thus, the relatively androgenic norethisterone acetate shows adverse effects while medroxyprogesterone acetate does not.50 As already indicated, it is probably the effects of the most widely used progestogens in opposed HRT that are responsible for the point of most general agreement in a controversial field—the importance of establishing the effects of opposed HRT on clinically manifest arterial disease. Indeed, one review51 concludes 'that adding an adequate dose of synthetic progestogen' to oestrogen replacement therapy 'is likely to significantly reduce the beneficial effects on risk of IHD'. With growing interest in lipoprotein (a), it is worth noting that a recent report52 suggests a beneficial—i.e. lowering—effect due to conjugated oestrogen and medroxyprogesterone acetate.

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Blood pressure It is on the relationship between HRT and blood pressure that data from properly controlled studies of adequate size are so far generally not available. Serial observations after the initiation of HRT, not properly controlled by measurements in comparable individuals not taking HRT, are unsatisfactory because of the habituation effect of repeated blood pressure measurements. Subjects whose pressures are frequently measured over a period of time become accustomed to the procedure and their initial pressures usually fall, often to a surprisingly large extent. Thus, uncontrolled studies reporting no increase in blood pressure after HRT has been started may actually have demonstrated a pressureraising effect of HRT, since habituation would lead to a fall. Haemostatic variables In a review several years ago,53 increases in fibrinogen and in the activities of factor VII and factor X and decreases in antithrombin III were the most consistently observed effects due to oestrogens. The implications of these changes are considered in further detail later. Functional Oestrogen probably improves blood flow in a number of vascular beds, an effect that may however be abolished by progestogens.54'55 OESTROGEN AND CARDIOVASCULAR DISEASE An obvious puzzle is the apparently different effects of oestrogen on the risk of cardiovascular disease in different settings. The question is worth considering, first, because of the light possible answers may throw on the most appropriate use of oestrogens in particular settings, including the use of HRT and, secondly, for the knowledge this kind of enquiry may provide about hormonal influences on the pathogenesis of arterial disease in general. The effect of oral contraceptives is to increase the risk of thromboembolism, to which both the oestrogen and progestogen contribute.1 The apparently protective effect of oestrogen in unopposed HRT is in obvious contrast. Another indication of the likely

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protective effect of oestrogen is the lower incidence of IHD before compared with after the menopause. Finally, in men the use of oestrogen for the treatment of cancer of the prostate clearly increases the risk of thromboembolism,56 though the very high doses and the different types of oestrogen used in this condition should be noted, with the obvious limitations this may impose on comparisons with HRT in women. At the same time, the findings on prostatic cancer do come from a randomised comparison, thus providing an additional reason for not unreservedly accepting the conclusion that unopposed HRT confers a very large benefit against IHD and stroke. Can any of the apparent anomalies in these comparisons be explained and, if so, what are the implications? The hormonal effects at the time of the menopause that influence cardiovascular disease are assumed to be due to the fall in oestrogen levels. However, very little is known about the possible effects of the substantial if shorter-term changes in gonadotrophins, so it should not automatically be assumed that only oestrogens are responsible for changes in the incidence of vascular disease. Hitherto, attempts to reconcile the apparent anomalies raised by the associations of oestrogen with vascular disease have been considered mainly in terms of the effects of oestrogen on lipid metabolism. Some progress may be possible by also taking account of differences and changes in the haemostatic system influencing coagulability and thus the thrombotic contribution to arterial disease. There is now little doubt that high levels of plasma fibrinogen, in particular, and also of factor VII activity, VIIC, influence the onset of clinically manifest arterial disease in men.57"61 High fibrinogen levels are now also known to be associated with an increased risk of IHD in women.60 High fibrinogen levels may lead to IHD through effects on atherogenesis itself, blood viscosity, platelet aggregability and the amount of fibrin deposited. Factor VII is a component of the extrinsic coagulation system which, it is increasingly recognised, exerts a major effect on the activation of other coagulation factors and on thrombin production. Several studies now provide consistent evidence on the effects of the menopause on coagulability. Table 4 summarises clotting factor and cholesterol levels in women at entry to the Northwick Park Heart Study (NPHS) according to their menopausal status.62 The difference in cholesterol levels was no longer significant after allowance was made for the correlations between VIIC and cholesterol. The difference in VIIC according to menopausal status has also been reported by others.63

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Table 4 Mean age-adjusted clotting factor and cholesterol levels in 833 women according to menopausal status 60 Premenopausal (n = 364)

Postmenopausal (n = 469)

Factor VIIC (%)

105.1

115.9

Fibrinogen (g/1)

2.85

3.02

Cholesterol (mmol/1)

5.91

6.26

All difference*. P-0.002 or lesi

The cross-sectional findings in Table 4 have now been confirmed prospectively in women according to the occurrence or otherwise of the menopause during the 6-year follow-up period.64 These results are shown in Table 5. In those who continued to have periods, there were no increases in VIIC or fibrinogen. In those undergoing a natural menopause, there were highly significant increases in both clotting factors and in cholesterol. VIIC and fibrinogen also increased in the smaller number of women undergoing an artificial menopause, although the effects were not statistically significant at a conventional level. The difference between those experiencing a natural or artificial menopause was significant (P = 0.03) for fibrinogen but not at a conventional level for VIIC. The difference was also significant for cholesterol. In women whose menopause was artificial, ovarian conservation may partly explain the smaller average increase in clotting factors and cholesterol than in those whose menopause was natural. The increase in cholesterol found in those undergoing the menopause has also been described in an American group of women65 in whom the changes in individual lipoproteins would be expected to increase the risk of IHD. Neither NPHS (unpublished) nor the American study found significant changes in blood pressure associated with the occurrence of the menopause. Figure 1 illustrates antithrombin III levels in NPHS participants. Antithrombin III, as its name implies, neutralises thrombin activity and also reduces the activity levels of other clotting factors, particularly factor X. In men, there is a steady decline from the age of about 40 onwards which may imply diminishing capacity to deal with the increase in pro-coagulatory factors, including VIIC and fibrinogen, that occurs with age. Among pre-menopausal women, values are lower than in men of the same age. However, the menopause is accompanied by an increase in antithrombin III levels so that post-menopausal women have the highest values.

to 00

o

Table S Mean-age adjusted clotting faaor and cholesterol levels during 6-year follow-up period by menopausal status 62 Continued penods (n=136) Entry Faaor VIIC(%)

102.8

Menopause Artificial (n = 28)

Natural (n = 69)

Follow up 101.9

Entry

Follow up

Entry

Follow up

107.4

121.2

99.5

106.6

Fibrinogen (g/1)

2.76

2.80

2.84

3.31

2.81

3.03

Cholesterol (rnmol/1)

5.46

5.34

6.05

6.69

5.50

5.55

with nituitl menop«u*e: P< 0.0001 (tec also text)

j>

HRT AND CARDIOVASCULAR DISEASE

299

96949290c

ithi

E P

8886-

c

84-

8280J r 20

30

40

50

60

70

80

Age (years) Fig. 1 Annthrombin III levels in NPHS participants. Prc-menopausal women (A); post-menopausal women (B); men ( • ) . (Reproduced by permission of the Editor of the British Journal of Haematology).

This potential protection against thrombosis in post-menopausal women may be of some importance bearing in mind the marked increase in coagulability due to the menopause, summarised in Tables 4 and 5. The higher values of antithrombin III in postthan pre-menopausal women have also been reported by others.66 OC, which increase the risk of thromboembolism, are used at ages when antithrombin III levels are relatively low. Consequently, there may be some impairment of capacity to counteract oestrogen-induced changes in the haemostatic system4 favouring thrombosis. HRT, on the other hand, is mostly used by postmenopausal women among whom antithrombin III levels are higher and may, by counteracting the increased coagulability produced by HRT, allow oestrogen-only preparations to exert a protective effect through their influence on lipid profiles. Older men have the lowest antithrombin III levels. These naturally low levels, compounded by a further lowering of antithrombin III and an increase in coagulability due to oestrogens in the treatment of prostatic cancer,67 might partly explain the increase in thrombotic events in these circumstances. These suggestions—still speculative in many respects—are summarised in Table 6, along with the effects of oestrogens on the

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Table 6 Summary of effects of oestrogens on coagulability and thrombotic events, and natural and/or oestrogen-induced antithrorabin III levels Coagulability

Antithrombin III

Events

I T I 1 T

low high low high low

T 1" 1

Oral contraceptives Hormone replacement Menopause:' pre v. post post v. pre Cancer of prostate *Oe*trogen-oo]y prepartnom b Effccti uiumed to be doe to octtrogcni

r T

coagulation system. The findings for the menopause are shown both as a comparison of pre- compared with post-menopausal women (since it is in the former group that higher oestrogen levels occur, corresponding to the administration of oestrogens in OC and to HRT for prostatic cancer) and as a comparison of postand premenopausal women, which is how the effects of menopause are usually thought of. Any generalisation about oestrogens and thrombosis is clearly impossible, but an approach based on protective, antithrombotic mechanisms may help resolve some of the anomalies. An interesting point for further study is whether HRT may be contraindicated in those with low antithrombin III levels. CLINICAL IMPLICATIONS To summarise, unopposed oestrogen (mainly in the form of Premarin) probably confers a worthwhile degree of protection against IHD, though it may be prudent at least to question whether this amounts to as much as the 20-25% lower incidence in users compared with non-users suggested at face value by the studies reviewed. However, this conclusion is mainly applicable to the minority of menopausal patients who have undergone hysterectomy and in whom there is thus no added risk of uterine cancer. The decision as to which preparation to prescribe in the much larger proportion of patients who have not undergone hysterectomy depends on the balance between several potential benefits and hazards, about which there is inadequate evidence. If progestogens do reduce the apparently cardioprotective effect of unopposed oestrogen, the argument for using unopposed preparations in patients who have not undergone hysterectomy should at least be considered—and, to a much greater extent than hitherto, by patients as well as their doctors. IHD and stroke are the leading causes of death and serious illness in post-menopausal women.

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301

Consequently, the possible benefits of unopposed HRT in women who have not undergone hysterectomy almost certainly outweigh the hazards of uterine cancer in numerical terms. There are, of course, other considerations. One is the understandably emotive nature of cancer at any site, even though the prognosis for treated uterine cancer is generally good. If, for an individual patient, the avoidance of cancer is more important than the numerically greater benefit in terms of cardiovascular disease, this is clearly the basis on which her treatment should be decided. But she should surely have as much to do with this decision as anyone else. There is also the undoubted problem of monitoring the nonhysterectomised patient taking unopposed HRT for the investigation of irregular bleeding and the detection of early neoplastic changes, with all the implications for the patient and for gynaecological and other services. But these difficulties are not necessarily insuperable. Oestrogen monitored by regular endometrial biopsy is common practice in the USA68 so that the use of unopposed HRT in non-hysterectomized patients should not be automatically ruled out. The most systematic attempt to estimate the overall effects of opposed and unopposed regimes in hysterectomised and non-hysterectomised women is shown in Table 7, based on the analysis by Ross et al.69 It cannot be emphasised too strongly that this analysis depends on a number of so far unvalidated assumptions, as the authors themselves point out. It does, however, suggest a larger mortality reduction in non-hysterectomised women due to unopposed oestrogen than to opposed treatment. The same is true for hysterectomised women. Obviously, it is the assumptions about the effects of progestogens on cardiovascular Table 7 Estimated changes in annual mortality induced by HRT, unopposed or opposed (i.e. with progestogen), for 10 days a month, for 10 years67 Condition

Annual mortality rate/100 000 an

Osteoporotic hip fractures Endometrial cancer Breast cancer Ischaemic heart disease Stroke Net change Non-hysterectomised Hysterectomised

ages

oj-11

55 42 102 592 98

Change in mortality/ 100 000 Unopposed -33

Opposed -33 0 + 38

+ 26 + 38 -284

-184

-49

-32

-302 -328

-211 -211

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risk which have particular influence on the numbers derived, further emphasising the urgency of direct evidence. That this kind of analysis is not simply academic is supported by the use of unopposed oestrogen in non-hysterectomised patients by some general practitioners in the United Kingdom (and discussed in further detail below). Very recently, it has been suggested that opposed HRT may also substantially reduce the risk of myocardial infarction.70 However, the study in question has so far been published only in abstract form. For comparison with the number of observed events, expected numbers were apparently derived from pupulation-based figures, an approach which not infrequently leads to relatively low incidence figures in the index group (in this instance, the HRT users) because of selection effects. This report, which does have the advantage of coming from a prospective study, is at variance with thefindingof one of the case-control studies, already reviewed, specifically designed to distinguish between opposed and unopposed HRT.25 For the time being, therefore, opposed treatment in most nonhysterectomised patients is the conventional wisdom but the inadequate evidence for this approach should be appreciated. RESEARCH IMPLICATIONS What is the best way of clarifying the outstanding issues, particularly the cardiovascular effects of opposed HRT? The difficulties of observational studies have already been summarised. Nevertheless, one approach would be through further cohort studies, comparing IHD and stroke incidence in those taking opposed or unopposed preparations. Among the potentially confounding effects in studies of this kind, perhaps the most serious is the strong association between the type of HRT and hysterectomy status. Thus, the large majority of women who have not undergone hysterectomy are prescribed opposed HRT while those who have undergone the operation generally receive unopposed treatment. But there is little doubt that hysterectomy increases the risk of cardiovascular disease.71 This may be true not only for those whose ovaries are removed at the same time but also for those whose ovaries are conserved, in many of whom a functional oophorectomy may result from the effects of surgery on ovarian blood supply. Consequently, the close association between type of HRT and hysterectomy status is likely to make it particularly difficult to distinguish between the influences of the

HRT AND CARDIOVASCULAR DISEASE

303

former on subsequent cardiovascular disease. The problem would be lessened if there were adequate numbers of nonhysterectomised women receiving unopposed HRT and of hysterectomised women receiving opposed HRT—both of which occur (though not to a marked degree). Even then, the question would arise as to whether there were differences between those receiving opposed or unopposed treatment, within each group according to hysterectomy status, that might still confound the relationship of treatment with outcome. So are randomised controlled trials (RCTs) of HRT feasible? The need for these trials has recently been highlighted and considered in some detail72 through enquiries in 1989 and 1990 to 1081 doctors in 220 group practices throughout die United Kingdom in the Medical Research Council's General Practice Research Framework. These doctors were prescribing HRT to about 9% of their female patients aged between 40 and 64. Over half were prescribing opposed HRT to more patients than a year previously, emphasising the trend towards this approach and also the need for its evaluation. The majority would consider HRT for the prevention of osteoporosis (62%) and cardiovascular disease (57%) in patients not requiring treatment for menopausal symptoms. Among those who would not do so, uncertainty about long term effects coupled with the need for further evidence was the commonest reason. Based on an adaptation of the figures shown in Table 7, using mortality rates in England and Wales, the doctors in the Framework were then asked whether they would be prepared to enter patients into three RCTs. One (Trial A) would be a comparison of opposed and unopposed treatment in nonhysterectomised women, the second (Trial B) a comparison of HRT compared with no treatment (active treatment being determined by hysterectomy status, i.e. opposed treatment for those who had not undergone hysterectomy, unopposed for those who had) and the third (Trial C) a comparison of opposed and unopposed HRT in women who had undergone hysterectomy. There are greater or lesser difficulties with each. Trial A is clearly the most controversial, involving as it does the use of unopposed treatment in non-hysterectomised women and therefore a risk of uterine cancer alongside, on the other hand, the possibility of a considerable reduction in cardiovascular disease for those on unopposed treatment. Trial B may raise the fewest difficulties, the most obvious being the technical point that treatment could not be double-blind for non-hysterectomised participants in whom the occurrence or absence of cyclical bleeding would soon reveal

o O

Table 8 Three possible trials of HRT and % general practitioners (GPs) definitely or probably willing to enter patients

tn

Trial Opposed or unopposed HRT in nonhysterectomized women

Advantages Direct comparison of effects of opposed and unopposed treatment

HRT or no HRT in women free of menopausal symptoms. Opposed HRT for non-hysterectomized, unopposed for hysterectomized, compared with no HRT Opposed or unopposed HRT in hysterectomized women

Answers pragmatic question of effects of HRT regime appropriate to hysterectomy status on long-term outcomes Direct comparison of effects of oposed and unopposed treatment. Compliance likely to be high

Drawbacks Clinical and resource implications of increased incidence of uterine cancer due to unopposed treatment Comparison of effects of opposed and unopposed regimes indirect. Treatment allocation not blind in nonhysterectomized Provides answers for only minority of menopausal women. Acceptability of opposed HRT uncertain

% GPs willing 49

n

86

79

HRT AND CARDIOVASCULAR DISEASE

305

which group (active or placebo) they were in. Otherwise, however, there is a real question about the balance of possible benefits and hazards following the long-term use, or not, of HRT. In trial C, compliance would probably be high. The main question for resolution is the use of opposed treatment in hysterectomised patients. There are three reasons why this may be justified. First, 18% of the Framework doctors did sometimes prescribe opposed oestrogen to women who had had a hysterectomy, a practise also in accord with other, less formal evidence. Secondly, opposed HRT may be somewhat more effective than unopposed treatment in preventing bone loss, though this is by no means certain. Thirdly, the effects of progestogens (and oestrogens) on the incidence of breast cancer remain to be fully clarified. Some observational studies give cause for concern in the longer term73 while more theoretical considerations suggest that progestogens might confer some protection against breast cancer by analogy with their effect on the risk of uterine cancer. The responses of the Framework doctors are shown in Table 8. About half would enter patients into Trial A. Much higher proportions would do so for the other two trials. Based on these results, feasibility assessments of Trials B and C are now in progress, hopefully to be followed by the full trials that are undoubtedly needed.8 REFERENCES 1 Meade 1W, Greenberg G, Thompson SG. Progestogens and cardiovascular reactions associated with oral contraceptives and a comparison of the safety of 50- and 30 jig oestrogen preparations. Br Med J 1980; 1: 1157-1161 2 Kay CR. Progestogens and arterial disease: evidence from the Royal College of General Practitioners' Study. Am J Obstet Gynecol 1982; 142: 762-765 3 Bradley DD, Wingerd J, Petitti DB, Krauss RM, Ramcharan S et al. Serum high-density-lipoprotein cholesterol in women using oral contraceptives, estrogens and progestins. N Engl J Med 1978; 299: 17-20 4 Meade TW, Chakrabarti R, Haincs AP, Howarth DJ, North WRS, Stirling Y. Haemostatic, lipid and blood pressure profiles of women on oral contraceptives containing 50 ug or 30 ug oestrogen. Lancet 1977; ii: 948-951 5 Khaw KT, Peart WS. Blood pressure and contraceptive use. Br Med J 1982; 285: 403-407 6 Thompson SG. Observational studies of anticoagulants in the short-term secondary prevention of ischaemic heart disease. In: Meade TW, ed. Anticoagulants and myocardial infarction. New York: John Wiley, 1984: pp. 179-202 7 Armitage P. Clinical trials in the secondary prevention of myocardial infarction and stroke. Thromb Haemost 1980; 43: 90-94 8 Vandcnbroucke JP. Postmenopausal oestrogen and cardioprotection. Lancet 1991; 337: 833-834 9 Coope J. Postmenopausal oestrogen and cardioprotection. Lancet 1991; 337: 1162 10 Petitri DB, Perlman JA, Sidney S. Noncontraceptive estrogens and mortality: long-term follow-up of women in the Walnut Creek study. Obstet Gynecol 1987; 70: 289-293 11 Ross RK, Pike MC, Henderson BE, Mack TM. Oestrogen replacement therapy

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