The Women s Health Initiative where are we a decade later?

The Women s Health Initiative where are we a decade later? Henry G. Burger MIMR-PHI Institute & Jean Hailes for Women s Health, Melbourne, Australia Disclosures: Henry Burger Sources of Funding Pharmaceutical Companies Honoraria or consulting fees for lectures, advisory board chairmanships National Health and Medical Research Council Research support for studies on the endocrinology of menopause World Health Organisation Chairmanship of scientific group on research on the menopause Recent Relevant Statements Post Menopausal Hormone Therapy: an Endocrine Society Scientific Statement. Santen RJ et al, J Clin Endocrinol Metab 2010, supp 1, S1-S66 Updated IMS recommendations on postmenopausal hormone therapy and preventative strategies for midlife health. Sturdee DW and Pines A on behalf of the International Menopause Society Writing Group. Climacteric 2011;14:302-320. The Women s Health Initiative A Decade of Progress, Climacteric, vol.15:june 2012 Global Consensus Statement on Menopausal Hormone Therapy. De Villiers TJ et al. Climacteric 2013: 16:203-4 1

The major issues regarding menopausal hormone therapy A World Health Organisation Scientific Group Meeting in 1994 stated inter alia: In epidemiological studies, therapy with oestrogens alone produces a marked reduction in risk of coronary heart disease (CHD). Date on use of oestrogens plus progestogens is sparse and inconsistent. Use of oestrogen alone for <5 years appears to have no effect on risk of breast cancer. Addition of progestogen to oestrogen may be associated with an increase in risk. Mortality rates in women 2000 Rates per 100,000 1500 1000 500 Heart Disease Lung Cancer Breast Cancer 0 45-54 55-64 65-74 75-84 Age Source, ABS, Causes of Death, Australia, 1996 Cat. No. 3303.60 The WHI Hormone Therapy Trials (1) Two RCTs were done: combined, continuous daily therapy (CCT) with conjugated equine estrogen (CEE,0.625mg) and medroxyprogesterone acetate (2.5mg) in women with an intact uterus. CEE (0.625mg) alone in hysterectomised women Both were chronic disease prevention trials in older, postmenopausal women of average age 63 years, 70% overweight or obese, 50% hypertensive, 50% past or current smokers. 2

The WHI Hormone Therapy Trials (2) Two main questions were posed: Does a standard regimen of the hormones usually used to treat menopausal symptoms reduce cardiovascular risk? Does the treatment increase breast cancer risk significantly? Who Were the Participants? Predominantly healthy women (The WHI Investigators) Age 33% aged 50-59, 45% 60-69, 21% 70-79 BMI Smoking 70% (CCT) BMI >25, 34% >30 (i.e. obese) 79% (E only) 45% 50% past or current smokers Hypertension 36% (CCT), on treatment, or BP >140/90 48% (E only) Past or Current HT 26% (CCT) past or current hormone users 48% E only Therefore, which risks are applicable to symptomatic women? Comparison of subjects in the WHI Combined Continuous Trial and the Nurses Health Study Characteristic WHI Nurses Health Study Age range at enrolment (years) 50-79 30-55 Smokers (past and current) % 49.9 6.9 BMI (kg/m2, mean) 28.5 25.1 Aspirin users (percentage) 19.1 43.9 HRT regimen Continuous Unopposed Combined sequential Menopausal symptoms Largely Predominant Excluded 3

Relevance of Risks to Menopause Management An important criterion for the relevance of a RCT is that it is conducted in a population of subjects similar to those normally targeted for treatment. For the WHI hormone therapy (HT) trials, this criterion is not met. The investigators stated this trial did not address the short-term risks and benefits of hormones given for the treatment of menopausal symptoms. Short-term was not defined : taken here as therapy for <5 years. The initial announcement from the US Women s Health Initiative Randomised Controlled Trial of Hormone Therapy Menopausal hormone therapy CAUSES A 26% INCREASE IN BREAST CANCER. Such therapy also increases the risk of CHD. The announcement was made by PRESS CONFERENCE prior to publication and without the agreement of all investigators. Cardiovascular outcomes The primary outcome was designated as Coronary Heart Disease (CHD). The first report of the combined-continuous HRT RCT gave: HR for CHD 1.29 (1.02 1.63) 286 cases HR for breast cancer 1.26 (1.00-1.59) 290 cases (NS) Excess risk per 10,000 person years: 7 more CHD events, 8 more invasive breast cancers» Rossouw et al JAMA 2002 4

Applicability of results No noteworthy interactions with age were found for the effects..on CHD. It is noteworthy that the increased rate for cardiovascular disease was present across..age strata.» Rossouw et al JAMA 2002 Cardiovascular Disease A major reason to undertake the WHI trials was the observation of 40-50% cardiovascular disease risk reduction resulting from HT, particularly in the Nurses Health Study. The latter was an observational study, clearly subject to potential bias and confounding, but using data from mostly symptomatic American nurses treated at age shortly after menopause. Such women in general are at low CVD risk. As noted above, the WHI participants had a number of significant CVD risk factors including their age, BMI, smoking status, blood pressure and years since menopause. It was therefore very likely that many had subclinical atherosclerotic vascular disease. They are therefore not subjects from whom effects of initiating HT can be extrapolated to the usual target population. Cardiovascular Disease Conclusions The WHI trial results for CVD were consistent with experimental observations in primates (cynomolgus) that HT is protective against atherosclerosis when initiated immediately after oophorectomy, but is no longer protective after a two year delay. In WHI (CCT) HR for CVD risk was: 0.89 for women <10 years postmenopausal 1.71 for those >20 years postmenopausal In the E only arm, cardioprotection noted in those aged 50-59. Recent further analysis (Rossouw et al JAMA 2007) stated that in the 50-59 year age group, low or no absolute excess risks of CHD, stroke, total mortality..due to hormone therapy. There were 10 fewer deaths per 10,000 person years. The low or absent excess risk of CHD in women with <10 years since menopause may be somewhat reassuring.. Offer some reassurance that hormones remain a reasonable option for the short-term treatment of menopausal symptoms. 5

HRT and cardiovascular events in recently postmenopausal women: randomised trial Schierbeck LL et al., BMJ 2012: 345 e6409 (November) Open label, randomised controlled trial in 1006 healthy women, aged 45-58, recently postmenopausal or perimenopausal, 502 on HRT, 504 untreated contols. Treatment was with oral triphasic oestradiol ( E2) and norethisterone acetate (NA) ( 2mg E2 12 days, added NA 1mg for 10 days, 1 mg E2 6 days) n=407, or E2 2 mg daily for hysterectomised women N=95. At inclusion, average age 50, 7 months postmenopausal. Primary outcome was a composite of death, hospital admission for heart failure and myocardial infarction. HRT and cardiovascular events (2) After 10 years of randomised follow-up, primary outcome occurred in 18 on HRT 33 controls HR 0.48 (0.26-0.87 p=0.015) Mortality 15 vs 26 Breast cancer 10 treated, 17 control Conclusion: HRT associated with a significantly reduced risk of mortality, heart failure or myocardial infarction, without any apparent increase in risk of cancer, VTE or stroke. KEEPS - Kronos Early Estrogen Prevention Study Aim: to determine the effects of estrogen on atherosclerosis progression indices in early post menopausal women Design: 727 women were recruited, age 42-58, 6-36 months post menopausal. Given oral CEE 0.45mg per day or transdermal estradiol 50 mcg per day (+oral progesterone 200mg daily for 14 days) or placebo Measures: Primary-IMT and CAC Outcomes: No difference between groups for cardiovascular endpoints Conclusions: Four years early MHT did not affect atherosclerosis progression 6

ELITE: Early versus Late Intervention Trial with Estradiol Aim: To determine whether effect of estradiol on IMT differs depending on time since menopause Design: 623 women were recruited, either <6 or >than 10 years post-menopausal. Given oral estradiol 1 mg daily + vaginal progesterone Outcomes: results not yet formally published but preliminary reports suggest slower progression of IMT in the early post menopausal women Breast cancer Combined Continuous Therapy The press conference announcement that HT caused a 26% increase in breast cancer risk was the major reason for the widespread anxiety and abandoning of HT in June 2002. It is therefore important to examine this risk critically in terms of relevance to menopause management. Crucial to this assessment is the fact that: o 74% of CCT participants were hormone-naïve o 26% prior HT users There was no significant increase in risk (after 5.6 years) in the hormone-naïve participants : HR = 1.09 (0.86 1.39) (Anderson et al. 2006) There was an apparent increase in prior users, HR = 1.96 7

Breast cancer Estrogen Only Breast cancer risk was lower in estrogen users than in placebo users: HR = 0.77 (0.59-1.01) The decrease was actually significant in non-prior users. Noteworthy that in other observational studies, breast cancer risk on estrogen alone increases after 5 (Lyytinen et al. 2006) or >15 years (Chen et al. 2006). From: Health Outcomes After Stopping Conjugated Equine Estrogens Among Postmenopausal Women With Prior Hysterectomy: A Randomized Controlled Trial JAMA. 2011;305(13):1305-1314. doi:10.1001/jama.2011.382 Invasive breast cancer 0.05-0.04-0.03 - Cumulative Hazard 0.02-0.01 - Overall a Postintervention b 0.05-0.04-0.03-0.02-0.01-0 1 2 3 4 5 6 7 8 9 10 11 12 13 Years No. at risk CEE 5310 5166 5007 4840 4261 3620 1696 Placebo 5429 5280 5106 4915 4301 3678 1771 0 1 2 3 4 5 Years 4697 3635 3438 4756 3670 3459 Figure Legend: Vertical dotted lines represent quintiles of duration of intended intervention and follow-up in the study population (elapsed time from randomization until the end of the intervention on February 29, 2004). CEE indicates conjugated equine estrogens. a Includes events from randomization to August 14, 2009. b Includes events from March 1, 2004, to August 14, 2009. Copyright 2012 American Medical Association. All rights reserved. Breast Cancer Conclusions from WHI Combined HT may increase breast cancer risk after 5 7 years in non-prior users of hormone therapy. There was no evidence of a risk increase before that. However, time since menopause at which treatment is initiated may be important, with risk increasing earlier for initiation close to menopause. Estrogen alone in hysterectomised women may decrease breast cancer risk in the first five years, but ultimately an increase in risk may occur 8

Breast Cancer Overall Conclusions from RCT and Observational Studies No overall statement re risk of HRT is possible: For Australian women in the early postmenopause, absolute increase in risk may vary from 0 12 additional cases per 1000 women per five years Some forms of combined HRT may increase risk especially in lean women treated with Norethisterone or MPA Risk may increase after three years in those at highest risk Risk assessment is part of the overall consideration of the benefits and risks of hormone therapy 25 Lessons Learnt (1) Treatment trial results should not be released by press conference prior to publication. Use of relative risk (RR) rather than absolute risk (AR) may give rise to grossly distorted perceptions of treatment effects. For coronary heart disease (CHD), results do not apply across age strata as originally claimed. Quotations from WHI papers re CHD JAMA 2002: The increased risks for cardiovascular disease and invasive breast cancer were present across racial/ethnic and age strata.. JAMA 2007: There were no significant increases in risk due to hormone therapy for any outcome at ages 50 59 years, but increases in risk for CHD, stroke and global index events in some older age categories were noted. Obstetrics & Gynaecology 2013: As noted in the original Women s Health Initiative, oestrogen plus progestin therapy trial publication, the increased risks of cardiovascular disease and invasive breast cancer were present across all age strata. Conclusions from the use of oral CEE + MPA may not apply to transdermal E2 + progesterone or dydrogesterone. 9

Lessons Learnt (2) This large randomised trial was marked by high drop-out rates, 42% for HT, 38% for placebo, raising questions about the interpretation of results. The population was not selected as being at increased risk of fracture, despite which the HT decreased the hip fracture rate from 15 to 10 per 10,000 women per year the first trial with definitive data supporting the ability of postmenopausal hormone therapy to reduce the risk of fracture. HT also decreased the risk of colorectal cancer from 16 to 10 per 10,000 women per year. Lessons Learnt (3) In the light of the fracture data, it was predictable that an increased rate of fracture would be observed in women prematurely discontinuing their treatment: this has been documented in at least two reports. Whether an increased risk of CHD will also occur has not yet been documented, the recently published results of the Danish Osteoporosis Prevention Study suggest it may. Lessons Learnt (4) The investigators cautioned that this trial does not address the short-term risks and benefits of hormones given for the treatment of menopausal symptoms. Despite this, it was assumed universally that the results were applicable to symptomatic peri- and early postmenopausal women. 10

Lessons Learnt (5) The results for the oestrogen only trial were much more favourable, including cardioprotection, reduction in breast cancer risk and similar effects on fracture risk. Effects on venous thromboembolism were less. Therefore, questions were raised regarding the role of MPA and recent data suggests that progesterone and dydrogesterone are safer progestins. Lessons Learnt (6) The conclusions of the WHI investigators were that the risk-benefit profile found in this trial is not consistent with the requirements for a viable intervention for primary prevention of chronic diseases, and the results indicate that this regimen should not be initiated or continued for primary prevention of CHD. These remain valid for combined continuous HT with CEE and MPA. Whether this will be true for transdermal E2 with progesterone remains to be shown. Global Consensus-Menopausal Hormone Therapy (MHT) (1) MHT most effective treatment-benefits outweigh risks partic. <age 60, < 10 yrs since mp. Effective and appropriate for osteoporosis-related fracture prevention in same groups. Standard dose E-alone may decrease CHD and allcause mortality in same groups; combined MHT neutral. Local low-dose E for vaginal symptoms. E appropriate post-hysterectomy, P required if uterus intact. Option of MHT is an individual decision. 11

Global Consensus-Menopausal Hormone Therapy (2) VTE and ischaemic stroke risk increase with oral MHT but absolute risk rare <60. Observational studies point to lower risk with transdermal therapy. Breast cancer risk > 50 a complex issue-primarily associated with P addition. Risk is small, decreases after treatment stopped. Dose and duration of MHT should be individualised. In POI, systemic MHT recommended until average age of natural menopause. Use of custom-compounded bio-identical HT not recommended. Current safety data do not support use of MHT in breast cancer survivors. 12