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European Heart Journal Advance Access originally published online on August 9, 2006
European Heart Journal 2006 27(17):2046-2053; doi:10.1093/eurheartj/ehl183
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© The European Society of Cardiology 2006. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Randomized trial of effects of continuous combined HRT on markers of lipids and coagulation in women with acute coronary syndromes: WHISP Pilot Study

Peter Collins1,2,*, Marcus Flather3, Belinda Lees3, Rebecca Mister4, Anthony J. Proudler5, John C. Stevenson2,5 on behalf of the WHISP (Women's Hormone Intervention Secondary Prevention Study) Pilot Study Investigators

1 Cardiac Medicine, National Heart and Lung Institute, Imperial College London, Dovehouse Street, London SW3 6LY, UK
2 Department of Cardiology, Royal Brompton & Harefield NHS Trust, Sydney Street, London SW3 6NP, UK
3 Clinical Trials and Evaluation Unit, Royal Brompton & Harefield NHS Trust, London, UK
4 NH & MRC Clinical Trials Centre, University of Sydney, Sydney, Australia
5 Faculty of Medicine, Imperial College London, London, UK

Received 4 August 2005; revised 13 June 2006; accepted 14 July 2006; online publish-ahead-of-print 9 August 2006.

* Corresponding author. Tel: +44 20 7351 8112; fax: +44 20 7351 8771. E-mail address: peter.collins{at}imperial.ac.uk


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 Steering Committee
 Safety Committee
 Adjudication Committee
 Investigators
 Acknowledgements
 References
 
Aims Randomized trials have not demonstrated coronary heart disease benefit from hormone replacement therapy (HRT). We hypothesized that low-dose HRT may avoid harm.

Methods and results We studied the effects of HRT on lipids and coagulation in women with acute coronary syndromes. A total of 100 post-menopausal women >55 years were enrolled between 2 and 28 days after an acute coronary syndrome and randomized to oral oestradiol-17ß 1 mg plus norethisterone acetate 0.5 mg daily, or matching placebo, and followed for up to 12 months. Levels of lipids, lipoproteins, and haemostasis markers were measured at baseline, 3, and 6 months. There were no significant differences in lipid levels between the two groups, probably due to concomitant statin use. Antithrombin and factor VII levels were significantly lower in the HRT group, whereas fibrinogen was significantly decreased in the placebo group. No evidence of increased coagulation activation was observed, nor of adverse cardiovascular outcomes [odds ratio (OR) 0.63 (95% confidence intervals 0.31–1.31)].

Conclusion Low-dose HRT may give cardiovascular benefit. These findings require confirmation in a full clinical trial with evaluation of cardiovascular outcomes as the primary objective.

Key Words: CHD • HRT • Lipids • Haemostasis


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 Steering Committee
 Safety Committee
 Adjudication Committee
 Investigators
 Acknowledgements
 References
 
Coronary heart disease (CHD) is a major cause of morbidity and mortality in women. Loss of ovarian steroid hormones at the menopause appears to be linked to the increased risk of CHD1,2 generating the hypothesis that hormone replacement therapy (HRT) could potentially be of benefit in preventing CHD. The HRT modifies many metabolic risk factors for CHD,3 which would decrease the risk of atherogenesis, and oestrogen has direct effects on blood vessels which are potentially beneficial.4 Protective effects of hormone therapy have been reported in numerous observational studies.5,6 However, clinical trials of HRT have not shown a benefit on cardiovascular events in post-menopausal women, either with prior CHD7 or without prior CHD.8 Most of these studies have used conjugated equine oestrogens (CEEs) 0.625 mg daily, combined with medroxyprogesterone acetate (MPA), and have observed an early increase in CHD events, albeit with a later decrease. Different doses and types of oestrogens and progestogens have different metabolic effects, some of which may be less favourable than others for the cardiovascular system. Higher doses of oral oestrogens have the potential to increase coagulation activation and adversely affect vascular remodelling, both of which could produce early harm.9 We hypothesized that the use of low-dose oestrogen combined with a different progestogen may have a beneficial effect in acute coronary syndromes by avoiding early harm. We therefore evaluated the effects of a continuous combined low-dose HRT on lipids and markers of haemostasis, as well as overall safety and feasibility, as a prelude to a larger study to assess effects of HRT on clinical outcomes.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 Steering Committee
 Safety Committee
 Adjudication Committee
 Investigators
 Acknowledgements
 References
 
Patients
Details of inclusion and exclusion criteria are given in Table 1. At the start of the study, eligibility criteria restricted enrolment to post-menopausal women with a confirmed myocardial infarction (MI) between 2 and 7 days of presentation, but after 34 patients had been enrolled, eligibility was extended to include patients with non-ST elevation acute coronary syndrome up to 28 days after presentation. The main reason for modifying eligibility part way through the study was to improve enrolment. Ethical approval was obtained from the North Thames Multicentre Research Ethics Committee and the Local Research Ethics Committee at each centre. Written informed consent was obtained from all patients.


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  		Table 1 Eligibility criteria

 
Patients were randomized to HRT [continuous combined oral oestradiol-17ß 1 mg and oral norethisterone acetate (NETA) 0.5 mg daily (KliovanceTM, Novo Nordisk)] or placebo by telephone call to the co-ordinating centre. A blinded treatment pack was allocated to the patient. Study treatment was stratified by centre (blocks of four) and provided for a maximum of 12 months. WHISP was a multi-centre, prospective, randomized, double-blind, placebo-controlled pilot study. Seventeen hospitals throughout the UK participated in the study (see list of investigators and centres at end of this report).

Outcome measures
The aim of the study was to examine the (1) effects of HRT on lipids, and markers of coagulation and fibrinolysis, (2) feasibility of enrolling patients, and (3) safety and tolerability of HRT. Patients were followed-up at 3, 6, 9, and 12 months after the date of randomization (minimum follow-up 3 months). At each follow-up visit, clinical events, compliance to medication, possible side effects of the trial treatment, and general symptoms were recorded. Fasting blood samples for lipid and coagulation markers were collected at 3 and 6 months. Study treatment was discontinued for any of the following: suspected breast or endometrial cancer, clinical suspicion of thrombo-embolism, unacceptable side effects, or at the patient's request. Patients who had discontinued treatment were requested to continue with follow-up.

Laboratory analyses
An overnight fasting blood sample was taken for analysis of lipid (EDTA plasma) and coagulation markers (citrated plasma). Coagulation samples were separated into polypropylene cryovials prior to storage. Chilled tubes (4°C) were used to collect samples for prothrombin fragment 1+2 (F1+2) analysis. Samples were centrifuged at 4°C (3000 rpm) within 30 min, plasma were stored at –20°C prior to transportation to the central laboratory for subsequent assay. Plasma total cholesterol and triglycerides were measured using enzymatic procedures (ABX Diagnostics). HDL cholesterol was measured following heparin manganese precipitation of other lipoproteins. HDL sub-fraction 3 (HDL3) cholesterol was measured following further precipitation with dextran sulphate. HDL subfraction 2 (HDL2) cholesterol was calculated as the difference between HDL and HDL3 cholesterol. LDL cholesterol was calculated using the Friedwald formula. Apolipoproteins AI and B were measured with commercial immunoturbidimetric kits (Wako). Lipid assay performance was monitored using lyophilized human sera. Within- and between-assay percentage coefficients of variation were 0.9 and 1.5 (total cholesterol), 1.3 and 2.1 (triglycerides), 0.9 and 2.3 (HDL cholesterol), 1.6 and 4.2 (HDL3 cholesterol), 0.9 and 2.4 (apolipoprotein AI), and 1.5 and 2.0 (apolipoprotein B).

Samples for factor VII coagulation (VIIc) activity were thawed in a water bath (37°C) and then left at room temperature prior to analysis for a period not greater than 30 min prior to analysis. Plasma fibrinogen, factor VIIc activity and activated protein C (APC) resistance were measured by an ACL coagulometer (materials supplied by Instrumentation Laboratories). Plasma antithrombin activity was measured by chromogenic assay (Chromogenix). F1+2 and fibrin D-dimer were measured using commercial ELISA kits (Dade-Behring and Quadratech Ltd, IE). Coagulation assay performance was monitored using lyophilized and frozen human plasmas. Within- and between-assay percentage coefficients of variation were 3.2 and 6.5 (fibrinogen), 3.2 and 5.0 (factor VIIc), 0.8 and 3.2 (APC resistance), 0.9 and 4.4 (antithrombin), 6.0 and 7.5 (F1+2), 4.7 and 9.8 (fibrin D-dimer).

Statistical analysis
The sample size was determined from the observed LDL-cholesterol decreases with a continuous combined oestradiol-17ß/NETA (2 mg/1 mg) regimen in older healthy post-menopausal women.10 We assumed that there could be a lesser effect with the lower dose used in our study. Allowing for a 33% drop-out, a study of 50 patients per group would have 96% power to detect a difference of 0.3 mmol/L in LDL cholesterol between treatment and placebo after 3 months of treatment, assuming a standard deviation of 0.4 mmol/L, a correlation with baseline of r=0.5, and an alpha of 0.05.

For the blood results analyses, the distribution of each parameter was examined and normalized if necessary by logarithmic transformation. ANOVA was performed to examine treatment effects on laboratory parameters between the groups, using baseline values and statin use as covariates. We performed the comparisons of blood results using patients with complete values at baseline and 6 months. Imputation of missing values was performed using the last observation carried forward (LOCF) method. Pearson {chi}2 analyses and Kaplan–Meier survival plots were used to examine treatment differences in events and treatment compliance.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 Steering Committee
 Safety Committee
 Adjudication Committee
 Investigators
 Acknowledgements
 References
 
Between October 1999 and October 2001, 1851 women were screened for entry and 100 patients were randomized to HRT (49 patients) or matching placebo (51 patients; Figure 1). There were no significant differences in any of the baseline characteristics between the two groups (Table 2). The majority of patients were admitted with anterior (30.6% in HRT group vs. 35.3% in placebo group) or inferior (42.9 vs. 35.3%) MI. The number of patients admitted with unstable angina was similar (14.3% of patients in HRT group vs. 15.7% in placebo group). There were no differences in statin use at baseline or follow-up (22.4 vs. 25.5% on admission, 79.6 vs. 82.4% at discharge). There were also no differences at baseline between HRT and placebo groups in aspirin or other anti-platelet medication (37 vs. 29%), beta-blockers (22 vs. 25%), nitrates (22 vs. 24%), calcium antagonists (18 vs. 12%), ACE-inhibitors (12 vs. 14%), or diuretics (24 vs. 24%). Median (inter-quartile range) follow-up was 7 (3,12) months representing a total of 61 person years of follow-up. In total, 14 patients (29%) in the treatment group and 3 (6%) in the placebo group discontinued treatment for clinical reasons (Figure 1). Other reasons for withdrawal are presented in Figure 1. Thirty percent of patients underwent coronary angiography during the study, 16% underwent angioplasty, and 6% underwent coronary artery by-pass grafting. There were no significant differences between the treatment groups for these procedures.


Figure 1831
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  		Figure 1 Consort diagram.

 

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  		Table 2 Baseline characteristics

 
Effects on lipids
Table 3 shows the absolute values and differences between groups adjusted for baseline and statin use for each of the lipid markers, respectively. There were no significant differences between groups in lipid markers. Both groups showed reductions from baseline in total cholesterol and triglycerides, LDL cholesterol, and apolipoprotein B concentrations. Increases in HDL cholesterol and apolipoprotein AI were observed in both groups.


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  		Table 3 Lipid markers

 
Markers of coagulation and fibrinolysis
Table 4 shows absolute values and differences between groups adjusted for baseline and statin use for each marker of coagulation and fibrinolysis. A significant difference in fibrinogen was observed between the two groups at 3 months due to a fall from baseline in the placebo group with no change in the HRT group. This difference had disappeared by 6 months. Significant differences in factor VII concentrations between the two groups were observed at both 3 and 6 months, with a decrease from baseline with HRT at 3 months. There was a significant difference between the two groups in antithrombin at 3 and 6 months due to a decrease with HRT group. No differences were observed in APC resistance, F1+2, or fibrin D-dimer between the two groups.


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  		Table 4 Markers of coagulation and fibrinolysis

 
Clinical events, feasibility of enrolment, and safety
Table 5 shows the number of patients who had experienced an adverse event at 12 months post randomization. The rate of the composite outcome of death, MI, stroke was 8 and 16%, respectively for HRT and placebo and for death, MI, stroke, or cardiovascular hospital admissions it was 24 and 31%, respectively (HR 0.63, CI 0.31–1.31). There was no significant difference between any of the other adverse events (HR 0.59, CI 0.32–1.06). Figure 1 summarizes the reasons for discontinuation of study drug. The main reason for stopping treatment was at the patient's request rather than a recognized side effect. Of the 39 patients who stopped taking the treatment before the end of the study, 20 (51%) still attended all follow-up sessions, 12 from the treatment group and 8 from the control group. Therefore, 19 patients were lost to follow-up before the end of the trial. There was a significant difference between the discontinuation rates in the two groups. Patients in the HRT group were more likely to discontinue compared with those in the placebo group [HR 2.16 (1.11, 4.22) P=0.02]. Figure 2 shows the Kaplan–Meier estimates of the discontinuation rates for the two treatment groups.


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  		Table 5 Adverse events

 

Figure 1832
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  		Figure 2 Kaplan–Meier plot of discontinuation rates.

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
Steering Committee
 Safety Committee
 Adjudication Committee
 Investigators
 Acknowledgements
 References
 
Our results show that a low-dose continuous combined HRT regimen appears safe when given to post-menopausal women at high risk for cardiac events. There was no evidence of increased coagulation activation, but a reduction in the risk of a composite of cardiovascular events was shown although this was not significant.

In the Heart and Estrogen/progestogen Replacement Study (HERS),7 women assigned to daily oral CEE 0.625 mg plus MPA 2.5 mg experienced a higher rate of CHD events than those receiving placebo in the first year. Post-hoc analysis found a significant trend towards decreased risk in the treatment group thereafter. Over the entire 4.1-year study, no difference was found between the groups. The oestrogen–progestogen arm of the Women's Health Initiative (WHI) conducted by the National Institutes of Health in the United States randomized ~16 000 women to either combined continuous oestrogen (CEE 0.625 mg) and progestogen (MPA 2.5 mg) or placebo to evaluate the impact of HRT in the primary prevention of CHD.11 This arm of the study was stopped early due to the finding of a lack of overall benefit in selected clinical outcomes after a pre-specified safety limit on increased risk of breast cancer was breached. There was also an increase in cerebrovascular events,8 but the pattern of CHD events was similar to HERS, with early harm being followed by possible later benefit.12 The oestrogen-alone arm of WHI randomized ~12 000 women to either CEE 0.625 mg or placebo. Overall, there was no significant reduction in CHD events with this treatment, although there was a significant decrease in a composite of MI and coronary interventions.13

Why are our findings different from those of HERS? The metabolic effects of HRT differ according to the type and dose of oestrogen and progestogen, and to their route of administration. These metabolic differences are likely to be unimportant for some effects, such as on vasomotor symptoms or on the skeleton, but are clearly important for the cardiovascular system. CEEs with MPA produce reductions in LDL cholesterol and increases in HDL cholesterol, which would be regarded as beneficial for atheroma risk. However, they also produce increases in triglycerides, which are unwanted.14 At higher doses, combinations of oestradiol and NETA show reductions in LDL cholesterol and in triglycerides, which would be beneficial. But they also produce reductions in HDL cholesterol, which are unwanted.14 Our HRT regimen avoided the latter adverse effect. There were no apparent adverse effects of this HRT on coagulation activation as judged by the lack of increase in F1+2 and fibrin D-dimers. The transient fall in antithrombin levels with HRT has been noted previously, as has a fall in factor VII.15 Of importance, there were no increases seen with HRT in the other markers of susceptibility to venous thrombosis, such as APC resistance and fibrin D-dimers. This was reflected by the equal numbers of venous thrombo-embolic events seen with both HRT and placebo. One concern with some HRT regimens is that there may be an increase in venous, and possibly arterial, thrombo-embolism. This is usually an early event, and other studies of a different HRT regimen have suggested early harm.7,8 These studies used a relatively high starting dose of HRT for the patients’ age and found an increase in cardiovascular events in the first year of treatment with HRT, even though the incidence of these events has tended to decline in later years. This dose of oestrogen could be of initial harm to older women but of benefit to younger women.16 It is therefore of interest that those women in WHI on active treatment who were either closest to menopause or in the youngest age decade showed a decrease in events compared with the older groups.8,13 In our pilot study, we do not see any evidence of such an increase in events. We chose a low dose of a different oestrogen because adverse effects of HRT on coagulation activation appear to be dose-dependent and may vary with the type of oestrogen,17,18 and we appear to have avoided this risk. We did not measure inflammatory markers in our study. However, although oral HRT has been shown to increase C-reactive protein concentrations, the relevance of this is unclear because it also reduces the levels of various other inflammatory markers.19 The choice of progestogen may also be important for the cardiovascular system. MPA has been shown to negate the beneficial effects of oestrogen on vascular function,20,21 whereas our chosen progestogen, NETA, appears to have a much smaller negative effect.22 We observed a smaller number of cardiovascular events in the HRT group, although this reduction was not statistically significant. The CHD events in the WHI studies were fewer in those on CEE alone than in those on combined CEE plus MPA. The number of events in our study was much higher than those seen in the HERS secondary prevention study, probably reflecting the higher risk population we chose to study. Our WHISP patients were all within 1 month of an acute coronary syndrome, whereas the HERS population were all at least 6 months beyond their last cardiac event. Obviously, the HERS trial was a full study rather than a pilot study, with a much greater patient population studied over a longer time period.

Another randomized trial of transdermal oestradiol-17ß with or without transdermal NETA also failed to show benefit in women with CHD,23 but again the dose of oestradiol used (80 µg per day) was high for the age of the patients. In contrast, a randomized trial using the relatively lower dose of oral oestradiol 1 mg daily showed a non-significant reduction in coronary deaths during the first 12 months of study.24

It has been suggested that only relatively healthy arteries will respond to HRT, and this could explain the apparent benefit in younger women but lack of response in older women.25 This concept is supported by primate data,26 but there are findings in humans, which show that diseased arteries can respond to oestrogen.27,28 Our study would support these findings.

Two main difficulties with our study were encountered. First, it proved to be difficult to recruit patients into the trial. Only 5% of patients screened were eventually enrolled in the study. Sixty percent of patients screened were ineligible for the study, and of those eligible only 13% were actually enrolled. However, this compares favourably with the published recruitment rates of other randomized trials of women with CHD. For example, the Estrogen Replacement and Atherosclerosis trial screened 73 327 women to recruit 309,29 an uptake rate of <1%. The main reason for low recruitment was refusal to take part in the trial. Secondly, the adherence to therapy was relatively poor. In the HRT group, 22% of patients discontinued because of side effects. These difficulties could be in part due to the unfamiliarity of local investigators with HRT, as they were not experienced in menopause and HRT management. Future studies may benefit from the involvement of local menopause clinicians with the cardiac teams, helping to improve both study uptake and treatment adherence.

In conclusion, the WHISP study has demonstrated that a low-dose HRT regimen can be given safely to post-menopausal women with acute coronary syndromes. No adverse effects on coagulation activation were observed. The lack of an early increase in cardiovascular events was in contrast to that seen in a previous secondary prevention study using a different HRT regimen, suggesting that the dose and type of HRT regimen may be critical in determining benefit or harm for the cardiovascular system. Full clinical trials of alternative HRT regimens are clearly needed.


   Steering Committee
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Steering Committee
Safety Committee
 Adjudication Committee
 Investigators
 Acknowledgements
 References
 
Professor Thomas Meade (Chair), Professor David Barlow, Professor Simon Thompson.


   Safety Committee
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Steering Committee
 Safety Committee
Adjudication Committee
 Investigators
 Acknowledgements
 References
 
Professor Rory Collins (Chair), Dr Jean McEwan, Mr Malcolm Whitehead


   Adjudication Committee
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Steering Committee
 Safety Committee
 Adjudication Committee
Investigators
 Acknowledgements
 References
 
Miss Janice Rymer, Mr David Sturdee


   Investigators
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Steering Committee
 Safety Committee
 Adjudication Committee
 Investigators
Acknowledgements
 References
 
Professor J Adgey & Ms L Swales, Royal Victoria Hospital, Belfast

Dr M Brack & Ms L Radford, Victoria Hospital, Blackpool

Dr A Bridges & Ms S Watt, Stirling Royal Infirmary, Stirling

Professor J Cleland & Mr A Fussey, Castle Hill Hospital, Hull

Dr J Davies & Ms W Covell, Royal Gwent Hospital, Newport

Dr I Findlay & Ms J Dougall, Royal Alexandra Hospital, Paisley

Professor K Fox, Dr D Newby & Ms L Smyth, Royal Infirmary of Edinburgh, Edinburgh

The late Dr W Hendry, Dr P Clifford, Mr J Scurrell, & Ms J Wiltshire, Wycombe General Hospital, Wycombe

Dr S Hutchinson & Ms J Hillman, Nevill Hall Hospital, Abergavenny

Dr G Jackson & Ms A Cooper, St Thomas’ Hospital, London

Dr P Mahy & Ms D Hughes, Torbay Hospital, Torquay

Dr R Mattu & Ms L Gill, Walsgrave Hospital, Coventry

Dr K Morris & Ms M Marriott, Nottingham City Hospital, Nottingham

Dr T Mourant & Ms J Bennett, Royal Cornwall Hospital, Truro

Dr I Starkey & Ms A Morrison, Western General Hospital, Edinburgh

Dr M Seed & Ms R Mandeno, Charing Cross Hospital, London

Co-ordinating centre (Clinical Trials and Evaluation Unit, Royal Brompton Hospital, London): Belinda Lees, Rebecca Mister, Marcelo Shibata, Fiona Nugara, Marcus Flather


   Acknowledgements
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Steering Committee
 Safety Committee
 Adjudication Committee
 Investigators
 Acknowledgements
References
 
We are grateful to Marcelo Shibata, Duo Lao Wang, Simon Thompson and Michael Roughton for their help with the study design and statistical analyses and Carolyn Webb for her invaluable help in completing this manuscript. The UK Medical Research Council provided a grant to support the study (Grant G9811667). Novo Nordisk provided funding for laboratory analyses and also provided the study drug.

Conflict of interest: P.C. reports having served as a consultant to Eli Lilly, Berlex, Merck, Pantharei and Pfizer, paid lecture fees by Berlex, Merck, Pfizer, Novo Nordisk and Organon, grant support from Eli Lilly, Organon and Merck. M.F., B.L., R.M., A.J.P. have no conflicts of interest. J.C.S. has, in the past 5 years, received research grants from Women's Health Concern and the Peninsular and Orient Steam Navigation Company; served on Advisory Boards and/or received honoraria for lectures from AstraZeneca, Wyeth, Novo Nordisk, Servier, Orion, and Theramex; is currently the Chairman of the charity Women's Health Concern, Executive Council member of the British Menopause Society, and member of the Scientific Advisory Board, National Osteoporosis Society; has previously been Chairman, British Menopause Society, Executive Committee Member of the International Menopause Society and of the European Menopause and Andropause Society, and Treasurer of the U.K. Bone and Tooth Society; is an Editor of Maturitas and serve on the Editorial Boards of Osteoporosis International, Practical Cases on Menopause, Journal of British Menopause Society, and Practical Cardiovascular Risk Management; and is a member of the International Scientific Committee, Revista Colombiana de Menopausia, and Non-US Section Head, Cardiovascular diseases in women (reproductive and post-reproductive age), Women's Health Faculty, Faculty of 1000 Medicine.


   References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 Steering Committee
 Safety Committee
 Adjudication Committee
 Investigators
 Acknowledgements
 References
 

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