A study of hormone replacement therapy in postmenopausal women with ischaemic heart disease: the Papworth HRT Atherosclerosis Study

BJOG: an International Journal of Obstetrics and Gynaecology September 2002, Vol. 109, pp. 1056 1062 A study of hormone replacement therapy in postmenopausal women with ischaemic heart disease: the Papworth HRT Atherosclerosis Study S.C. Clarke a, J. Kelleher a, H. Lloyd-Jones a, M. Slack b, P.M. Schofield a, * Objective To assess the possible benefit of hormone replacement therapy (HRT) in the secondary prevention of ischaemic heart disease. Design A prospective randomised trial of transdermal HRT in women with definite ischaemic heart disease. Setting A regional cardiac unit. Population Postmenopausal women with angiographically proven ischaemic heart disease. Methods A total of 255 postmenopausal women with angiographically proven ischaemic heart disease were recruited and randomised; 134 were treated with transdermal HRT and 121 acted as controls. The women were seen at six monthly intervals. The primary end points, which were determined by a blinded assessor, were admission to hospital with unstable angina, proven myocardial infarction or cardiac death. A total of 53 (40%) patients withdrew from the HRT group and eight (7%) from the control group. The mean duration of follow up was 30.8 months. Main outcome measures Admission to hospital with unstable angina, proven myocardial infarction or cardiac death. Results During follow up, there were 53 primary end-point events in the HRT group and 37 in the control group. Using an intention-to-treat analysis, the primary end-point event rate was 15.4 events per 100 patient years for the HRT group compared with 11.9 for the control group (event rate ratio 1.29 (95% CI 0.84 1.95, P ¼ 0.24)). Using a per-protocol analysis, there was an event rate ratio of 1.49 (0.93 2.36, P ¼ 0.11) for the HRT arm compared with the control arm. Particularly during the first two years of follow up, the HRT group had a higher, but not statistically significant, event rate than the control group. Conclusion Our findings suggest that transdermal HRT should not be commenced for the purpose of secondary prevention in postmenopausal women with angiographically proven ischaemic heart disease. INTRODUCTION Symptomatic ischaemic heart disease is less common in women than in men and is rare before menopause. This observation has generally been explained by the beneficial effect of oestrogens on the vascular tree and has been reinforced by several observational studies, which have suggested that hormone replacement therapy (HRT) reduces the risk of developing ischaemic heart disease 1 4. The majority of the non-randomised primary prevention studies have shown a lower mortality in the oestrogentreated group with relative risk ranging from 0.3 to 1.9. The largest studies both showed a halving of the incidence of fatal myocardial infarction in the treatment group. The Kaiser Permenante study enrolled over 16,000 healthy a Papworth Hospital, Cambridge, UK b Hinchingbrooke Hospital, Huntingdon, UK * Correspondence: Dr P. M. Schofield, Papworth Hospital NHS Trust, Cambridge CB3 8RE, UK. D RCOG 2002 BJOG: an International Journal of Obstetrics and Gynaecology PII: S1470-0328(02)01544-6 women and showed a subsequent relative risk of 0.5 5. The Nurses Health Study enrolled over 48,000 individuals and had a similar relative risk of 0.5 6. The obvious problem with these studies is that they were non-random and the findings may be attributable to selection bias if the women who chose to take HRT were healthier and had a more favourable ischaemic heart disease risk factor profile than those who did not 7,8. There is fairly limited data regarding secondary prevention with oestrogens in established ischaemic heart disease. This is despite the fact that postmenopausal women with symptomatic coronary disease would seem to be a more attractive group than the healthy population for demonstrating a definite treatment effect. They have a much higher incidence of acute coronary events and seem to fare less well than men following myocardial infarction 9. There have been some observational studies which have included women with prior ischaemic heart disease: all of these found a beneficial association with postmenopausal oestrogen therapy 10 15. The Heart and Estrogen/Progestin trial was a randomised, prospective trial of oral oestrogen plus progesterone in postmenopausal women with established ischaemic heart disease 16. During an average follow up of www.bjog-elsevier.com

HRT IN POSTMENOPAUSAL WOMEN 1057 four years, treatment with combined HRT did not reduce the occurrence of non-fatal myocardial infarction or death from ischaemic heart disease. The study did not evaluate the effect of oestrogen alone. The Papworth HRT Atherosclerosis (PHASE) study is a prospective randomised trial of transdermal oestrogen or combined oestrogen/progesterone versus no therapy in postmenopausal women with angiographically proven ischaemic heart disease. METHODS The study population comprised of postmenopausal women who were admitted to Papworth Hospital for coronary angiography and were found to have significant ischaemic heart disease. Postmenopausal was defined as above 55 years of age and no natural menses for at least five years or previous bilateral oophorectomy. Significant ischaemic heart disease was at least a 50% stenosis (reduction in intraluminal diameter) in one or more major coronary arteries (left anterior descending, circumflex or right coronary vessels). Patients were excluded if they had a history of carcinoma of the breast or genital tract, a family history of breast cancer, undiagnosed postmenopausal bleeding, cholelithiasis, untreated hypertension (systolic pressure > 180 mmhg or diastolic pressure > 100 mmhg) or any previous abnormal cervical smear test. Consecutive women who satisfied the inclusion/exclusion criteria were invited to participate at the time of their admission for cardiac catheterisation. Data collected during one of our previous antioxidant trials 17 suggested that 33% of the study population would have had a prior hysterectomy. Women with a previous hysterectomy were randomly allocated to oestrogen patch or no therapy in a 2:1 ratio. Women with no prior hysterectomy were randomly allocated to combined oestrogen/progesterone patch or no therapy in a 1:1 ratio. Thus, active treatment (HRT) was expected to be allocated in an overall 5:4 ratio. Within each subgroup (hysterectomy or not), randomisation was prestratified for cholesterol, blood pressure, smoking habit and proposed management (coronary artery bypass grafting, medical therapy or percutaneous transluminal coronary intervention) (Fig. 1). Oestrogen treatment alone was only used in women with prior hysterectomy because of lack of concern about the risk of endometrial hyperplasia and endometrial carcinoma 18 21. The oestrogen patch contained 17h-oestradiol 2.5 mg, which delivers the drug at around 80 Ag/patch/day (Ethical Pharmaceuticals, Ely, Cambridgeshire, UK). The patch is applied every four days and produces a sustained level of plasma oestradiol. The increased risk of endometrial cancer is ameliorated by the concurrent use of progestogen for 14 days of a 28-day cycle. Such a combination has been shown to reduce the risk to that of an untreated population 22. In women with an Fig. 1. Trial profile. intact uterus, four oestrogen-only patches (as above) were applied for the first 14 days, followed by four patches containing oestradiol and norethisterone. The patch contains 3 mg 17h-oestradiol and 4 mg norethisterone. It delivers 80 Ag/patch/day of oestradiol and 120 Ag/patch/day of norethisterone (Ethical Pharmaceuticals). Serum norethisterone levels rise steadily to a peak on day 10. Women were asked to continue with HRT for at least three years and three months following randomisation. Patients were seen initially at three months following randomisation and thereafter at six monthly intervals in a hospital outpatient clinic by a senior research nurse. This enabled an evaluation of compliance, an opportunity to provide further study medication, questions about possible drug side effects and the assessment of any outcome events. Compliance was assessed by counting the patches supplied and returned and was found to be greater than 95%. Blood was taken at these visits for routine haematologic and biochemical tests, including liver function tests and lipid measurements. At the time of randomisation, 64 (48%) patients in the HRT group and 56 (46%) patients in the control group were receiving treatment with a statin. Statin therapy was not commenced during the follow up period in the remaining patients. If a patient developed troublesome vaginal bleeding, they were assessed by a gynaecologist who was a member

1058 S.C. CLARKE ET AL. of the PHASE study team. Treatment was discontinued if the patient was unable to tolerate study medication, if they developed endometrial hyperplasia with atypia, endometrial or breast carcinoma, pulmonary embolism or active gall bladder disease. Women who withdrew from the study were still seen and assessed at the follow up time points. Outcome measures The primary end points in the study were acute coronary events: cardiac mortality, non-fatal myocardial infarction or hospitalisation with unstable angina. They have the advantage of being discrete end points readily defined by generally agreed criteria. Cardiac mortality included a fatal documented myocardial infarction, sudden death within 1 hour of onset of symptoms, sudden unwitnessed death out of hospital in the absence of other known cause and death associated with a myocardial revascularisation procedure. The diagnosis of non-fatal myocardial infarction was based on three clinical features: typical ischaemic cardiac symptoms, the presence of ECG abnormalities (ST segment elevation and/or the development of new Q waves) and a rise in cardiac enzyme levels (to greater than twice the upper limit of the normal range) 23. These data (hospital records, ECGs and cardiac enzymes) were reviewed by a cardiologist blinded to the patient s treatment group and a diagnosis of non-fatal myocardial infarction made if there were two out of the three clinical features present. The data were analysed in the same way for patients admitted to hospital with a diagnosis of unstable angina. A diagnosis of unstable angina was confirmed if the patient had typical ischaemic cardiac symptoms, transient ST segment depression and no significant rise in cardiac enzymes 24. Therefore, all of the primary end points (cardiac mortality, non-fatal myocardial infarction and hospitalisation with unstable angina) were determined by a blinded assessor. Statistical analysis/data monitoring From our previous experience, we had extensive data on postmenopausal women with angiographically proven ischaemic heart disease admitted to our cardiac unit 17.This allowed an assessment of the feasibility of the study as well as power calculations. In the control arm of the Cambridge Heart Antioxidant Study (CHAOS), postmenopausal women had a cardiac mortality rate of 2% per annum, a non-fatal myocardial infarction rate of 4% per annum and a hospitalisation with unstable angina rate of 12% per annum. The PHASE study population size required to detect an effect on primary end points was calculated to be 375 patients. This allowed 90% power to detect a negative result ( P < 0.05). The estimate was based on the assumption that the annual event rate in the placebo arm would be 18% and that HRT would reduce events to 12% per annum. The plan for the PHASE study was therefore to recruit 400 postmenopausal women with angiographically proven ischaemic heart disease and to carry out a randomised, prospective, open-label, blind end-point study of topical oestrogen or combined oestrogen/progestogen versus no therapy. The low drop-out rate (25 patients) was considered adequate as the primary outcome could be ascertained from patient records and did not require the patient to attend for the extra investigations. Therefore, it was likely to be available for all patients randomised, with the exception of those who withdrew permission for this kind of follow up. The major analysis compared the primary end points (cardiac mortality, non-fatal myocardial infarction or hospitalisation with unstable angina) among women randomised to HRT and women randomised to the control group using a Cox proportional hazards model. The analysis was by intention-to-treat, categorising women according to randomised treatment assignment regardless of compliance. A per-protocol analysis was also undertaken, which included only time and events occurring while patients were taking their allotted treatment (i.e. either HRT patches or no HRT). There was an independent data and safety monitoring committee for the PHASE study. All of Table 1. Patient characteristics. Control (n ¼ 121) HRT (n ¼ 134) Mean age (SD), years 67.0 (11.8) 66.3 (11.2) Vessel disease Single, n (%) 48 (40) 51 (38) Multivessel, n (%) 73 (60) 83 (62) Previous PTCA, n (%) 10 (8) 10 (8) Previous CABG, n (%) 10 (8) 12 (9) Mean age menarche (SD), years 13 (1.7) 13.3 (1.8) Post-hysterectomy, n (%) 57 (47) 49 (44) Post-oophorectomy, n (%) 20 (17) 29 (22) History of menorrhagia, n (%) 67 (55) 74 (55) Family history of IHD, n (%) 68 (56) 69 (51) Diabetic, n (%) 16 (13) 17 (13) Non-smoker, n (%) 83 (69) 77 (57) Ex-smoker, n (%) 24 (20) 33 (25) Current smoker, n (%) 14 (12) 24 (18) Units alcohol/week, mean (SD) 1.82 (3.44) 2.24 (4.28) BMI, mean (SD) 26.9 (8.7) 26.2 (8.1) Mean systolic/diastolic BP 140/79 136/79 Total cholesterol, mean (SD), mmol/l 6.3 (1.4) 6.1 (1.3) HDL-cholesterol, mean (SD), mmol/l 1.18 (0.38) 1.14 (0.36) LDL-cholesterol, mean (SD), mmol/l 4.27 (1.46) 3.98 (1.19) Triglycerides, mean (SD), mmol/l 1.99 (1.12) 1.98 (1.23) HRT ¼ hormone replacement therapy; SD ¼ standard deviation; PTCA ¼ percutaneous transluminal coronary angioplasty; CABG ¼ coronary artery bypass grafting; IHD ¼ ischaemic heart disease; BMI ¼ body mass index; BP ¼ blood pressure.

HRT IN POSTMENOPAUSAL WOMEN 1059 Table 2. Events recorded intention-to-treat analysis. Year Control HRT UA MI Cardiac death Total events Follow up (patient years) Events per patient year (%) UA MI Cardiac death Total events Follow up (patient years) Events per patient year (%) 1 18 2 1 21 118.8 17.7 26 1 4 31 130.7 23.7 2 10 2 0 12 100.2 12.0 15 0 1 16 108.3 14.8 3 3 0 0 3 62.6 4.8 3 0 0 3 69.8 4.3 4 1 0 0 1 28.5 3.5 2 0 1 3 35.5 8.5 Overall 32 4 1 37 310.1 11.9 46 1 6 53 344.3 15.4 HRT ¼ hormone replacement therapy; UA ¼ unstable angina; MI ¼ myocardial infarction. the serious adverse events were reported to the group. Prior to starting the PHASE study, it was agreed to carry out an interim analysis of the results once over half of the patients had been randomised. The findings of this interim analysis are the basis of the PHASE trial reported here. The advice of the monitoring committee was to close the study once the findings from the interim analysis became available and to inform the patients and their doctors of the results. The authors accepted this advice. RESULTS A total of 255 women were recruited. Of these, 134 were randomised to the HRT group (58 to oestrogen only and 76 to combined therapy) and 121 to the control group. Two women were found to have exclusion criteria after randomisation but before treatment. Because there was no follow up of events, these women have been assigned zero follow up time. The mean duration of follow up was 30.8 months in both the HRT group and the control group. The clinical details of the patients are shown in Table 1. The groups were well matched and there were no significant differences between the groups in these variables. Primary end points There were eight (6%) deaths in the HRT group and three (2%) in the control group. Of these, two deaths in each group were due to non-cardiac causes. The number of events observed in up to four years of follow up is summarised in Table 2. The most frequently observed events were hospitalisation due to unstable angina and these occurred predominantly in the first two years after recruitment to the trial. The HRT group had an excess in these years and overall. Over the four-year period, the average event rate for the HRT group was 15.4 events per 100 patient years, compared with 11.9 for the control group. This represents an event rate ratio of 1.29 (95% CI 0.84 1.95, P ¼ 0.24) for the HRT arm compared with the control arm (i.e. 29% increase in events on HRT). There was no difference in the event rate between the oestogen-only patients and the oestrogen/progesterone patients, which were therefore combined for comparison with the control group. There were no significant differences between the groups in frequency of any cardiac event although the HRT group had higher rates in all events except non-fatal myocardial infarction. The Kaplan Meier estimates of the cumulative Table 3. Reasons for withdrawal from study treatment. Control (n ¼ 8) HRT (n ¼ 53) Prescribed HRT elsewhere (4) Vaginal bleeding (15) Breast cancer (1) Fluid retention (8) Patient felt non-specifically unwell (1) GP recommended (7) Low-bone density (1) Abdominal pain (3) No reason given (1) Entry criteria not satisfied (2) DVT (2) Abnormal hysteroscopy (1) Breast cancer (1) Breast tenderness (1) Skin irritation (1) Headaches (1) Other (11) Fig. 2. Incidence of cardiac events. HRT ¼ hormone replacement therapy; GP ¼ general practitioner; DVT ¼ deep vein thrombosis.

1060 S.C. CLARKE ET AL. incidence of the primary end points in the two groups are shown in Fig. 2. A total of 53 (40%) patients withdrew from HRT treatment (including the two who failed to start) and eight (7%) control patients withdrew, including four who independently had HRT prescribed. The reasons for stopping HRT are shown in Table 3. Those who were assigned to the HRT group stopped using patches a median of 206 days after randomisation (range 0 976) and controls started using HRT at median 267 days (range 25 433). The perprotocol analysis results in the exclusion of five events and 21.1 patient years of follow up in the control group and 14 events and 107.8 patient years of follow up in the HRT group. Using a per-protocol analysis, there were 32 primary end-point events in the control group and 39 in the HRT group, resulting in overall events per 100 patient years of 11.1 and 16.5, respectively. In this analysis, the effect of HRT in increasing the rate of cardiac events is increased slightly, but the qualitative interpretation remains unchanged. The exclusion of these data did not substantially alter the results or conclusions. Using a per-protocol analysis, there was an event rate of 1.49 (0.93 2.36 P ¼ 0.11) for the HRT arm compared with the control arm. Fig. 3. Percent changes in lipid profiles for HRT and control groups. Other outcomes As can be seen in Table 3, the most common reason for withdrawal from HRT treatment was vaginal bleeding. In the study, two patients developed breast cancer; one in the control group and one in the HRT group. One patient had an abnormal hysteroscopy and withdrew from HRT treatment and two patients stopped HRT following the development of a deep vein thrombosis. Five patients in the HRT group developed a transient ischaemic attack or a non-fatal cerebrovascular event as compared with three patients in the control group. During the trial, there was a fall in total cholesterol levels and LDL cholesterol levels in both the HRT group and the control group, but there was no significant difference between the two groups (Fig. 3). There was an increase in HDL cholesterol levels during the trial in both groups with again no significant difference between the two groups (Fig. 3). DISCUSSION The results of the PHASE study suggest that transdermal HRT does not reduce the risk of acute coronary events cardiac mortality, non-fatal myocardial infarction or hospitalisation with unstable angina in postmenopausal women with angiographically proven coronary artery disease. This finding is at variance with the many observational studies, which have suggested that oestrogens reduce the risk of ischaemic heart disease. It is consistent, however, with many of the findings in the HERS trial 16. The results of the observational studies may be influenced by the fact that women who use postmenopausal HRT have a more favourable ischaemic heart disease risk factor profile 25,26. This selection bias is present in all of the observational studies 10 15, which also tended to assess the effect of oestrogen therapy alone. Some observational studies, however, did evaluate the use of combined oestrogen and progesterone HRT and, in general, found a reduction in the rate of ischaemic heart disease as compared with the control group 3,26 28. Many of the observational studies of postmenopausal HRT have recruited patients who were healthy and younger than those in the PHASE study 1,2. Patients in the PHASE study had angiographically proven ischaemic heart disease. Similarly, patients in the HERS trial 16 were older, had evidence of ischaemic heart disease and were treated with combined oestrogen and progesterone: they did not experience a reduction in non-fatal myocardial infarction or cardiac death as compared with the control group. In the PHASE study, transdermal oestrogen (in patients with prior hysterectomy) and transdermal oestrogen/progesterone were used for HRT, whereas in the HERS trial, oral oestrogen and medroxyprogesterone were given to all

HRT IN POSTMENOPAUSAL WOMEN 1061 patients in the active treatment group. Oestrogens may potentially reduce the risk of ischaemic heart disease by their beneficial effects on serum lipid and arterial endothelial function 29 32. Some of the beneficial effects of oestrogen may be attenuated by the concurrent administration of progesterone 33. Although medroxyprogesterone has been shown to impair the oestrogen-associated increase in HDL cholesterol levels 34, it was found that the increase in endothelial-dependent brachial artery vasodilatation demonstrated following oestrogen therapy in postmenopausal women with ischaemic heart disease was identical to that following combined oestrogen/progesterone therapy 35. However, this was using norethisterone rather than medroxyprogesterone. In the PHASE study, patients treated with HRT demonstrated a fall in total cholesterol and LDL cholesterol levels accompanied by a rise in HDL cholesterol. These changes, however, were also present in the control group. It has been suggested that the beneficial effect on cholesterol metabolism observed with oral oestrogen does not occur with the transdermal preparations 36. We did not find any difference in the event rate of the three primary clinical end points between the oestrogen-only patients and the combined oestrogen/progesterone patients. It is interesting to note that the acute coronary events, particularly hospitalisation with unstable angina, tended to occur in the first two years after randomisation. This may reflect the fact that, at the time of their cardiac catheter study, patients were in a more active phase of their coronary artery disease. There was a trend for the event rate to be higher in the HRT group in the first two years, although this did not reach statistical significance. This observation may be due to some early prothrombotic or proischaemic effect of HRT. The beneficial effects of HRT on lipid profiles may not manifest themselves clinically for some time, as the influence on coronary atheromatous plaques will not be immediate. In the trials of lipid-lowering agents, the delay before ischaemic heart disease risk is reduced has been up to two years 37 39. It is interesting to note that in the HERS trial 16, the combined HRT regime appeared to increase the risk of cardiac death and non-fatal myocardial infarction in the first year of treatment but to decrease risk in subsequent years. Although this time trend should be interpreted with caution, this pattern of early harm followed by later benefit could account for some of the differences seen between the observational studies and the PHASE and HERS trials. The patients who developed problems early after starting HRT may not have been eligible for inclusion into the observational studies, which are not designed to detect an early adverse effect. In observational studies, both oestrogen 40,41 and combined oestrogen/progesterone 42,43 HRT have been shown to be associated with an increased risk of venous thromboembolism. This adverse effect was also found in the HERS trial 16. We observed a trend towards increased thromboembolic events in the HRT group. In the PHASE study, there were only two patients who developed breast cancer one in the control group and one in the HRT group. It has been suggested from observational studies that postmenopausal HRT with oestrogen alone for up to five years is not associated with an increased risk of breast cancer. Treatment for longer periods, however, may be associated with a small increase in risk 44. In the PHASE trial, there was a high dropout rate of patients in the HRT group. This reflects the fact that HRT is often not well tolerated in this older patient population, whose mean age was 66 years. CONCLUSIONS In postmenopausal women with angiographically proven ischaemic heart disease, treatment with transdermal oestrogen (in those with prior hysterectomy) or combined topical oestrogen/progesterone (in those with an intact uterus) did not reduce the incidence of acute coronary events cardiac mortality, non-fatal myocardial infarction or hospitalisation with unstable angina. In fact, it may increase the incidence of acute coronary events by 30 50% Therefore, we do not recommend starting treatment with transdermal HRT for the purpose of secondary prevention in this patient group. In view of the trend towards early harm noted in the PHASE study, as well as the possible later benefit noted in the HERS trial, it may be appropriate for women already receiving HRT to continue. The PHASE study did not evaluate women without evidence of ischaemic heart disease. Acknowledgements The authors would like to thank the participants, the physicians and the cardiologists who referred their patients to the trial. The authors would also like to thank the Independent Data and Safety Monitoring Committee, which included D. L. Stone and L. D. Sharples (who, in addition, provided statistical support), and N. Stephens who contributed to the trial design. Research funding was provided by the Dr Scholl Medical Foundation and Ethical Pharmaceuticals. Administrative support was provided by J. Rigley. Contributors: S. C. Clarke, P. M. Schofield and M. Slack developed the trial design and planned and managed the study. J. Kelleher, S. C. Clarke and H. Lloyd-Jones carried out the research work. M. Slack provided gynaecologic advice and support during the research. S. C. Clarke performed the analyses with statistical support. All of the investigators were involved in the preparation of the manuscript. References 1. Stampfer MJ, Colditz GA. 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