1. Journal Club 12/02 Dr Stephen Newell

2. Current Problems in Pharmacovigilance October 2002 Safety update on long-term HRT

3. Coronary heart disease “The anticipated benefit of long-term use in preventing CHD, as suggested by observational studies, has not been supported by the RCT data.”

4. HRT and coronary heart disease in women: a review of the evidence Low AK, Russell LD, Holman HE, Shepherd JM, Hicks GS, Brown CA. Am J Med Sci 2002 Oct;324(4):180-4 CHD is the leading cause of death in women – especially post- menopausal women. The role of HRT in prevention of CHD has been considered for many years. Early epidemiological studies suggested that oestrogen has a potential cardioprotective role as pre-menopausal women have a decreased risk of developing CHD compared with men. Later observational studies showed a decrease of CHD risk in post-menopausal women on HRT.

5. Major medical organizations particularly in the USA encouraged HRT for CHD risk reduction, along with using HRT for other potential benefits (such as osteoporosis prevention). Unfortunately, recent clinical trials seem to raise questions rather than provide evidence of any protective role of oestrogen in CHD. Two recent studies – the Heart and Estrogen/Progestin Replacement Study Follow-up (HERS II) and the Women's Health Initiative (WHI) – have concluded that HRT has no role in primary or secondary prevention of CHD in women.

6. A study of HRT in postmenopausal women with ischaemic heart disease: the Papworth HRT atherosclerosis study Clarke SC, Kelleher J, Lloyd-Jones H, Slack M, Schofield PM. BJOG 2002 Sep;109(9):1056-62 OBJECTIVE: To assess the possible benefit of HRT in the secondary prevention of IHD. DESIGN: A prospective randomised trial of transdermal HRT in women with definite IHD. SETTING: A regional cardiac unit. POPULATION: Post-menopausal women with angiographically proven IHD. METHODS: 255 post-menopausal women with angiographically proven IHD were recruited and randomised; 134 were treated with transdermal HRT, 121 acted as controls. The women were seen at six monthly intervals. The primary end points were determined by a blinded assessor. 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.

7. 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, an event rate ratio of 1.49 (P = 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 post-menopausal women with angiographically proven IHD.

8. Stroke “Overall results from RCTs have shown an increase in the risk of stroke in HRT users.”

9. Venous Thromboembolism “The absolute risk associated with HRT is…higher.”

10. Medical issues and hormone replacement therapy Harris PF. Curr Womens Health Rep 2002 Oct;2(5):373-81 The debate surrounding post-menopausal HRT has become more contentious in the past decade. The relationship between HRT and venous thrombotic events has been confirmed, although the absolute risk is small. Evidence of a relationship between breast cancer and HRT is stronger.

11. RCTs reveal an association with cardiovascular events in women with known heart disease, a possibly diminished overall quality of life due to HRT, and worsening of urinary incontinence. There is also some evidence associating HRT with ovarian cancer. But longitudinal studies continue to demonstrate that over the long-term HRT use is associated with fewer cardiovascular events and a reduced risk of developing dementia. Future studies may show that a lower daily dose of HRT can reduce the risks while still providing benefit.

12. Breast Cancer “The known increased risk of breast cancer in HRT users has been confirmed.”

13. HRT and breast cancer (from Bandolier) K Nanda et al. Hormone replacement therapy and the risk of death from breast cancer: a meta-analysis. American Journal of O & G 2002, 186: 325-334. Systematic review using several electronic databases, reference reviews, and contacts with experts and HRT-manufacturing companies for any studies relating to use of HRT and death from breast cancer, without any language restriction. Included studies had to be original research on humans, with HRT use as exposure and death from breast cancer as the outcome. The study had to compare the risk of fatal breast cancer among healthy users with that of nonusers. Ten studies were found, ranging from over 1,000 breast cancer deaths to four, and mostly published in the late 1980s through the 1990s. The overall risk was not different for users and nonusers, with a relative risk ranging from 0.48 to 1.89. Most studies showed a reduced risk, but not significantly so.

15. Ovarian Cancer “Results indicate a small increased risk of ovarian cancer in hysterectomised women with long-term use of oestrogen-only HRT.”

16. Does HRT increase the risk of ovarian cancer? The Independent of 21/3/01 reported that 'women who take HRT for more than 10 years double their risk of ovarian cancer’. The evidence came from a large, prospective US cohort study that followed users and non-users of HRT over a 14-year period. The article gave a reasonably accurate report of the evidence but misleadingly quoted that 46,000 instead of 211,581 women took part in the study. Further, the figures quoted for the risk of ovarian cancer (1.7%) were taken from a survey of the general US population and were not from the research study. To state that the research shows that 3.4% of women taking HRT will be affected by ovarian cancer is misleading and incorrect. The newspaper article correctly highlighted a number of limitations with the study findings and referred to other research, which suggested a link between breast cancer and HRT.

17. The research evidence is based on a large cohort study, which suffers from a small number of potentially significant flaws which may have an impact on the study findings and limit its relevance to women currently taking HRT in countries outside the USA. A total of 944 deaths from ovarian cancer were recorded in the cohort of 211,581 women over the 14-year period of the study. Women who had ever used HRT were 1.2 times more likely to die from the ovarian cancer compared to women who had never taken HRT. This increased risk was mainly observed in women who were users of HRT at baseline. Such women were 1.5 times more likely to die from the disease compared to women who had never used HRT.

18. Both duration of use and the recency of therapy had an effect on the risk of dying from ovarian cancer. This appears to be a reasonable study of a large group of women in the US but suffers from a number of potential problems - information regarding the use of HRT was dependent on women's recollections over the 14-year period & 2079 women were unable to be followed up after 1988 due to insufficient data. There is some doubt about the applicability of the findings to women in the US and other countries who are currently taking HRT: – – Women receiving HRT 14 years ago were likely to be using oestrogen replacement therapy, however today many women take combined progesterone and oestrogen therapy, which is likely to have different effects. The researchers did not gather any information regarding the type of HRT being used. – – The women in the study were also not representative of the US population in general as they were more educated and affluent than the US population as a whole. – – In addition, the study findings may not be relevant to women in countries outside the US. Overall, the study supports an increased risk of ovarian cancer in this particular study population. However, further large long-term observational studies that are applicable to women currently taking HRT are required to confirm an association between HRT and ovarian cancer.

19. Indications for prescribing: Useful for menopausal symptoms for 2-3 years Longer term use for the prevention of osteoporosis

20. HRT and fracture risk (from Bandolier) Non-vertebral fractures occur in 1% of women every year in the decade after age 65, increasing to 5% a year in women over 85 years. Other treatments that increase bone mineral density reduce fractures. HRT in older women increases bone mineral density and therefore should help prevent fractures. A large case control survey seemed to confirm this with the key message being that HRT protects against hip fracture while it is being taken and for a few years afterwards. Continued protection needs continued use. What about (other) non-vertebral and vertebral fractures? The message from two meta-analyses of randomised trials is about the same, though perhaps not quite as strong. Using all trials there was a reduced risk of vertebral and non- vertebral fractures with HRT but a significant result was seen only in trials with a mean age of less than 60 years when starting HRT.

21. The randomised world is not without its imperfections: reflections on the Women's Health Initiative Study McDonough PG. Fertil Steril 2002 Nov;78(5):951-6 In May 2002, the Women's Heath Initiative (WHI) clinical trial, designed to clarify the risks and benefits of combination HRT, came to a premature halt. An interim safety review after an average follow-up of 5.2 years found that a combination of oestrogen and progestogen often prescribed to post-menopausal women increased the risk of invasive breast cancer, heart disease, stroke, and pulmonary embolism. The combination hormone therapy reduced bone fractures and colorectal cancer, but not enough to outweigh the other risks.

22. The WHI trial presents a challenge for patients, physicians, and epidemiologists, since many observational studies have shown cardiovascular benefits of long-term HRT. Another paper in the same journal reported an epidemiological study with a 13.4-year mean follow-up suggesting that oestrogen replacement therapy, when used alone for 10 years or more, increases the risk of ovarian cancer. The WHI study calls into question the long-term use of HRT in healthy women. The benefit of the temporary use of oestrogen in controlling disruptive symptoms of the menopause is not being contested. The evidence from the WHI study will need to be incorporated into medical decision making.

23. Evidence from randomised trials on the long-term effects of HRT Beral V, Banks E, Reeves G. Lancet 2002 Sep 21;360(9337):942-4 Overall, HRT users had a significantly increased incidence of: breast cancer stroke pulmonary embolism a significantly reduced incidence of: colorectal cancer fractured neck of femur but no significant change in: endometrial cancer coronary heart disease

24. Next steps? Probably moved more towards patient-centred vs. HRT for all Based on symptoms Also with discussion about long- term benefits and risks An NSF for the menopause?