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Rapid Responses: Rapid Responses published:
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Strange are the Ways of Nature.
- BM HEGDE (21 July 2002)
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Predetermined Hormone Dose Outcome
- William D Misner Ph.D. (21 July 2002)
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Should the WISDOM trial continue?
- David J Torgerson (22 July 2002)
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Cancer and Hormone replacement therapy
- E.C.G. Grant (24 July 2002)
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Why are commentators on WHI not mentioning.....?
- Peter R Bradley (24 July 2002)
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The case for long term HRT
- Tony M Mander, Dr Nicola Mullin (24 July 2002)
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Hormone replacement therapy
- Mike Dixon (25 July 2002)
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Better the devil you know?
- David R Cole (25 July 2002)
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Misleading interpretations and recommendations of WHI results
- Martina Dören, MD PhD (25 July 2002)
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Cook the Goose
- Des Spence, Glasgow G20 9DR (31 July 2002)
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Timing of risks of HRT
- Kevin S. Channer (1 August 2002)
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WHI Breast Cancer Results and Public Health Concern
- Eberhard M Greiser, Claudia Steding, Katrin Janhsen, Klaus Giersiepen (7 August 2002)
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BM HEGDE, VICE CHANCELLOR Manipal-576 119 India
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Dear Sir, The first sentence in the third paragraph of this editorial makes me feel that our "scientific" logic seems to be connected to our convenience! If female hormones have anything to do with the survival of the human species, why, on earth, did Nature alter its secretion after menopause? How did males survive two million years? My long experience in medicine has taught me one lesson. Whenever we go against Nature, the long term results are not in our favour. HRT for symptom relief, on a short term basis, is quite understandable; as it is our duty to "cure rarely, comfort mostly, but console always." However, when it comes to long term use to prevent future dangers, one is on a very wet wicket. Future predictions, based on patchy information of the initial state of the organism, rarely come true. Changing the initial state with drug interventions might not ( usually do not) hold good as time evloves in a dynamic system. With this background it does not look sensible to me that hormones in different form might still be good despite the fact the study referred to shows long term HRT in very bad light. Nature must have had valid reasons to restrict these hormones only to the reproductive phase of a woman's life. Exogenous supply after Nature has chosen to limit might do more harm than good. It may not be out of place here to note that the normal menstrual cycle that depends on an ultradian, rhythm is dependent on the gravitational pull of the Moon! Nature has a reason for everything, but our reasoning might not be able to unravel the mystery many a time! yours ever, bmhegde |
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William D Misner Ph.D., R & D Director E-CAPS Inc.
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With the recent questions being discussed related to hormone activity in pre- and post- menopause subjects, why are we not predeterming what hormone and dose establishes normal reference range for each patient? The implication that excess estrogen or an imbalanced in the proper ratio of estrogen to progesterone suggests that before a low dose hormone be given to a patient entering menopause that dose be established to support the normal reference range in each specific subject. One hormone elevated has the potential to create a cascade of systemic events that may predispose degenerative disorders. What explication supports prescribing hormone replacement treatment without first determining that the specific dose written establishes a safe normal reference range for each individual patient? |
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David J Torgerson, Reader in Health Services Research Department of Health Sciences, York University
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The Women's Health Intiative (WHI) [1] study refered to by Stevenson and Whitehead is a landmark trial in many ways. It confirms the supremacy of large trial data with clinical outcomes over the use either observational data (which is subject to selection bias) or trial data with non-clinical outcomes, such as changes in lipids or bone density. It is interesting that the oestrogen only component of the WHI study continues, suggesting the adverse effects of HRT is due to medroxyprogesterone acetate (MPA) component of oestrogen plus progestin arm of the trial. Stevenson and Whitehead make the sensible suggestion that women requiring opposed oestrogens should use forms of HRT that do not incorporate MPA. Will the Medical Research Council's WISDOM HRT trialists follow this advice? The WISDOM trial, I believe, uses 5mg of MPA as opposed to the 2.5mg in the WHI study (with similar doses of oestrogens). One could always have questioned the wisdom of closely replicating the WHI study when, as Stevenson and Whitehead point out, there are many different forms of HRT that urgently require evaluation. It may be sensible therefore for the WISDOM study to alter its form of HRT whilst there are relatively few woman years of exposure to the 5mg dose of MPA. Indeed, it is difficult to envisage how current recruitment and retention of participants can proceed unless the HRT type is changed. If the current HRT is retained it is also difficult to see what added evidence the large and expensive WISDOM study can now contribute. If it confirms the WHI trial we will still not be in a position to consider other forms of HRT. If it comes to an opposite conclusion then the situation will be still confused as two large trials coming to different conclusions will not produce a clear cut answer to a pressing clinical question. 1 Writing group for the Women's Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women. JAMA 2002; 288: 321-333. David Torgerson has received funding and honoraria from a number of pharmaceutical companies including HRT manufacturers. |
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E.C.G. Grant, Physycian and medical gyaecologist 20 Coombe Ridings, Kingston-upon-Thames, Surrey, KT2 7JU
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Stevenson and Whitehead’s BMJ Editorial Hormone replacement therapy EDITOR - The Editorial by Stevenson and Whitehead minimises the importance of the WHI Study’s results.1,2 The surprise is not that progesterone causes breast cancer but that progestogens have been prescribed to millions of women for the last 40 years. Bilateral oophorectomy has been a treatment and preventative of premenopausal breast cancer since1896. 3 Progesterone causes breast and ovarian cancer in mice and dogs.4 Progestogens are breast carcinogens because they act predominantly like progesterone. Medroxyprogesterone acetate is mostly used for HRT in the USA, while norgestrel derivatives or norethisterone (norethindrone) are used for contraception in the USA and for both contraception and HRT in the UK. Medroxyprogesterone acetate (MPA) is a third less powerful than norethisterone, while levonorgestrel is five times more powerful.5,6 Weaker progestogens, like MPA, are given in higher doses and vice versa. In most studies scarcity of genuine “never” users of any type of hormone helps to minimise incidence and mortality risk estimates for all adverse effects. Most women in the WHI study had previously used contraceptive or menopausal hormones. They were re-enrolled for at least 3.5 years and 42% of takers discontinued HRT before the study was halted. Median length of use was not given but the risk estimates nearly doubled when nonadherence was taken into account. The study is therefore most useful for showing that current use increases the main causes of death, namely: breast cancer, coronary artery disease, strokes and pulmonary emboli. The study was stopped prematurely to prevent the inevitable increases in mortality with further HRT exposures. Dr Ellen C G Grant 20 Coombe Ridings, Kingston-upon-Thames Surrey KT2 7JU Email ellencggrant@onetel.net.uk 1.Stevenson JC, Whitehead MI. Hormone replacement therapy. BMJ 2002;325:113-114. 2. Writing Group for the Women’s Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomised controlled trial. JAMA 2002; 288: 321-33. 3. Beatson G T. On the treatment of inoperable cases of carcinoma of the mamma. Suggestions for a new method of treatment with illustrative cases. Lancet 1896;ii:104-107. 4.Li JJ Perspectives in hormonal carcinogensis. In Cellular and Molecular Mechanisms of Hormonal Carcinogenesis: Enviromental influences. Ed. James Huff, Jeff Boyd, J.Carl Barrett 1996 Wiley-Liss Inc. 5. Grant ECG. The Hormone Balance of Oral Contraceptives. The Journal of Obstetrics and Gynaecology of the British Commonwealth 1967; 74: 908- 918 6. Swyer GIM, Little V. Potency of progestogens and oral contraceptives: Further delay-of-menses data. Contraception.1982;26;23. |
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Peter R Bradley, General Practitioner Springwood, QLD, 4127
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I sincerely hope it (The WISDOM study) does continue. The more I examine the WHI figures the more I feel all it has done is muddy the waters. Why are commentators not addressing the obvious flaws? For example; The average age on entry was 63.2 yrs - 66% were between 60 and 79, meaning the figures are largely those of women who have already suffered significant accelerated degenerative changes before they got the replacement. We may slow the clock, but we cannot turn it back - that is all these figures showing negative effects on cardiovascular disease would seem to show. Add the fact that with an oestrogen dependent tumor you would expect them to be growing faster locally, being picked up earlier, (thereby improving the outcome by removal before metastasis one might well infer - other studies support that), and therefore giving the illusion early on of increased incidence. If only they had recruited more newly menopausal women, and continued it longer? Consider also the fact that elderly women untreated are hypo- coagulable if anything - they bleed easier, ask any anaesthetist, - think about their GI susceptability to NSAIDs - which might well mean their favoured status re thrombo-embolism is the perverse effect of a lower than normal thrombosis incidence. We may never know now, and this is serious. We really need to know the truth here, but with this study, I find myself wondering why they bothered? Two thirds of them were already out the stable door. This may well be a case of 'the Emperor's clothes.' |
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Tony M Mander, Gynaecologist University of Manchester, Academid department of Obstetrics and Gynaecology, Oxford Road, Manchester, Dr Nicola Mullin
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Editor - Following the editorial of Stevenson and Whitehead and the case for long term HRT(1) . The United Kingdom median age at menopause is 51 years. By 2025 there will be 13.6 million menopausal women, 42% of the female population; over 2 million over 80 years of age and 27,000 over 100 years of age (2). A 50 year old woman has a 39.7% lifetime chance of a hip, spine or forearm fracture. 1 in 3 women will develop osteoporosis over the age of 50 in the UK. Osteoporotic fractures cause disability and financial burden. At present the disease costs the NHS and government approximately £1.7 billion each year. Extrapolating this to 2025, results in 5.4 million largely preventable osteoporotic fractures in the UK. Costs of dementia in England and Wale were £5.35 billion for women using 1994 population figures. Extrapolated this to 2031, costs rise to £11.20 billion(3). Meta-analysis of observational studies on the effect of oestrogen therapy on the risk of developing dementia strongly suggests that oestrogen has a role to play in preventing dementia(4). Recent experimental work shows that oestrogen affects brain organisation for memory in postmenopausal women. Control studies provide compelling evidence that exogenous oestrogens enhance and maintain verbal and visual memory, and also improve aspects of social and physical function. Effective preventative strategies are needed to counteract this massive burden of disease caused by hypo-oestrogenism in later life. It is important to get the beneficial effects of oestrogen without the negative effects. Some of the excellent recommendations of the Pennell Report have been reflected in the emerging National Service Frameworks (NSFs) for Older People, Mental Health, Coronary Heart Disease and Diabetes (5). Early individual assessment and advice is crucial as tomorrow’s 80 year old is now 55. Primary Care Organisations (Primary Care Trusts and Primary Care Groups) have a duty to formulate preventative strategies and support General Practitioners in their implementation. There is a need for evidence base on the menopause to include areas relative to the NSFs, including: dementia and Alzheimer’s disease, osteoporosis, cardiovascular disease, falls, balance, exercise, eye sight, dentition and urogenital ageing. Unless preventative strategies relating to the menopause are embarked upon, the NHS Plan will be shipwrecked on a demographic iceberg, treating established disease which should have been prevented. Tony M Mander, Gynaecologist Nicola H Mullin, Clinical Lecturer, University of Manchester, Academic Department of Obstetrics and Gynaecology, Manchester References: 1. Stevenson JC and Whitehead MI. Hormone Replacement Therapy. BMJ 2002; 325: 113-114. 2. United Kingdom population projections. Office for National Statistics and Government Actuary’s Department, UK, 15.11.2001. http//www.gad.gov.uk 3. McNamee P. Costs of dementia in England and Wales in the 21st Century. Brit J Psychiatry 2001;179:61-266. 4. Mander AM. Oestrogen replacement and cognitive function. Reviews in Gynaecological practice. Summer 2001;1(2):100-107. 5. Department of Health (1999). NHS Plan. The Stationary office. London. Competing interests: AM has given invited lectures at meetings sponsered by pharmaceutical companies. |
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Mike Dixon, Consultant Surgeon and Senior Lecturer Edinburgh Breast Unit, Western General Hospital, Edinburgh, EH4 2XU
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The Women’s Health Initiative (WHI) randomised trial of HRT has resulted in two contrasting leaders, one in the BMJ by Stevenson and Whitehead (1) and the other in JAMA by Fletch and Colditz (2). Stevenson and Whitehead point out that the increased risks of breast cancer are small but they do not mention that during the study 42% of women taking active drug and 38% of those receiving placebo stopped the assigned medication, whereas Fletcher and Colditz report that the intention to treat analysis “may have underestimated the true effects and that if the duration of treatment is important as appears to be the case with breast cancer and if compliance decreases over time then five year results may underestimate long term treatment effects”. Stevenson and Whitehead state because the risk of breast cancer is not appreciably increased within the first few years of use women with short term menopausal symptoms should be reassured but there must be an interval between applying an agent which increases breast cancer risk and to cancer manifesting clinically so the four year gap may well represent a period during which cancers caused by the oestrogen take to develop and become clinically apparent. Both leading articles point out that the number of adverse events were small although Fletcher and Colditz do note that the adverse events add up and over the 5.2 years of the trial the excess numbers of events in the active drug group was approximately one for ever 100 women. The BMJ editorial states “long term HRT therapy could still be considered for prevention of osteoporosis” whereas the JAMA editorial finishes with the definitive statement “do not use oestrogen/progestin to prevent chronic disease”. The leader in the BMJ states “we do not yet know the effects if any of HRT for the prevention of dementia although preliminary evidence is encouraging”. This contrasts with a review published only last year by Manson and Martin in the New England Journal of Medicine (3) who state “although a number of early observational studies suggest that the cognitive dysfunction or Alzheimer’s disease is less likely to develop in women who take estrogen after menopause, more recent observational studies have failed to support this hypothesis (4) and a recent randomized clinical trial failed to demonstrate any benefit of estrogen therapy as treatment for mild-to-moderate Alzheimer’s disease (5)”. Further randomized data from the HERS study (6) also failed to show any benefit of HRT on cognitive function. I am surprised that Stevenson and Whitehead believe that these data are encouraging. We await with interest further information from the Women’s Health Initiative which is evaluating the role of HRT in the prevention of memory loss and cognitive decline. Both Smith in his editor’s choice (7) and Stevenson and Whitehead point out that in the WHI study there has been no effect as yet on mortality but as the authors of the original paper report the WHI study “could not address the risk due to breast cancer due to the relatively short follow up time”. Statements on mortality are therefore of questionable value. . As the JAMA leader points out “the results of the WHI study are consistent with the growing body of literature on the effects of the combination of estrogen and progestin”. Stevenson and Whitehead may be correct that the dose (and possibly type) of oestrogen and the type of progestogen may be crucial in determining the effects of combined preparations but as stated so eloquently by Ross and Pike “the burden of proof should no longer be on the epidemiologists and other investigators to demonstrate that it (combined HRT) increases the risk of breast cancer, rather it should shift to the proponents of their use to demonstrate that they do not” (8). There remains much that is uncertain in this area and contrasting views in two leading articles in two major journals one week apart make it even more difficult to put forward a coherent and consistent message following the WHI study to our patients. 1. Stevenson JC, Whitehead MI. Hormone replacement therapy. BMJ 2002; 325: 113-114. 2. Fletcher SW, Colditz GA. Failure of estrogen plus progestin therapy for prevention. JAMA 2002; 288. 3. Manson JE, Martin KA. Postmenopausal hormone replacement therapy. N Eng J Med 2001; 345: 34-40. 4. Grodstein F, Shen J, Pollen DA et al. Postmenopausal hormone therapy and cognitive function in healthy older women. J Am Geriatr Soc 2000; 48: 746-752. 5. Mulnard RA, Cotman CW, Kawas C et al. Estrogen replacement therapy for treatment of mild to moderate Alzheimer disease: a randomized controlled trial: Alzheimer’s Disease Cooperative Study. JAMA 2000; 283: 1007-1015. 6. Grady D, Herrington D, Bittner V et al for the HERS Research Group. Cardiovascular disease outcomes during 6.8 years of hormone therapy: Heart and Estrogen-progestin Replacement Study Follow-up (HERS II). JAMA 2002; 288: 49-57. 7. Smith R. Editor’s choice. BMJ 2002; 325 (20th July). 8. Ross R, Pike MC. Effect of hormone replacement therapy on breast cancer risk: estrogen versus estrogen plus progestin (response). J Natl Cancer Institute 2000; 92: 1100-1101. |
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David R Cole, Consultant Physician Christchurch Hospital, Private Bag 4710, Christchurch, New Zealand
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Drs Stevenson and Whitehead state in their editorial that hormone replacement therapy as 625mcg conjugated oestrogens with medroxyprogesterone acetate at any dose should not be prescribed longterm in view of the Womens Health Initiative results. They indicate any regimen other than this is to be preferred. On what grounds? What equivalent data is there to show other regimens to be better? Who can be confident alternatives will not have greater adverse outcomes? At least there is data to indicate outcome risk from this regimen and, as commented earlier in the article, risk is very small indeed with overall mortality unchanged. Perhaps better the devil you know than the devil you don't. |
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Martina Dören, MD PhD, Free University, Benjamin Franklin University Hospital, Clinical Research Center of Women´s Health D-12203 Berlin, Germany
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One may wonder after the disappointing results of WHI (1), and previously the HERS study, both the initial (2) report and the unblinded follow-up study (3), how “long term therapy could still be considered for prevention of osteoporosis, used as part of the management of women with particular cardiovascular risk factors, and used for better quality of life”. It remains unclear, given the lack of evidence from comparably large, randomised, prospective, placebo-controlled trials with other estrogenic compounds than conjugated equine estrogens, and or other progestational drugs than medroxyprogesterone acetate, how to justify that in particular women with cardiovascular risk factors should use estrogen replacement therapy. Given the subanalyses published in JAMA (1), there was no subgroup that profited from the regimen studied. Furthermore, how should physicians explain to women that hormone replacement is obviously beneficial to reduce fractures at old(er) age, but there is an increase of breast cancer the longer she takes it ? As there are clearly effective pharmacological alternatives for the primary and, perhaps more importantly, secondary prevention of postmenopausal osteoporosis and effective non-pharmacological and pharmacological strategies to prevent and treat cardiovascular disease (4,5), I wonder whether the long-term indication of prevention of osteoporosis is a wise choice today given the lack of benefit of HRT for cardiovascular diseases. 1 Writing Group for the Women´s Health Initiative Investigators.Risks and benefits of estrogen plus progestin in healthy postmenopausal women. Principal results from the Women´s Health Initiative Randomized Controlled Trial. JAMA 2002;288:321-33. 2 Hulley S, Grady , Bush T, Furberg C, Herrington D, Riggs B et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. JAMA 1998;280:605-13. 3 Grady D, Herrington D, Bittner V, Blumenthal R, Davidson M, Hlatky M et al. Cardiovascular Disease outcomes during 6.8 years of hormone therapy. JAMA 2002;288:49-57. 4 AHA guidelines for primary prevention of cardiovascular disease and stroke: 2002 update. Circulation 2002;106:388-91. 5 MRC / BHF Heart Protection Study of cholesterol lowering with simvastatin in 20 536 high-risk individuals: a randomised placebo- controlled trial. Lancet 2002;360:7-22. |
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Des Spence, GP Maryhill Health Centre, Glasgow G20 9DR
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Dear BMJ I read with interest the influential Editorial on HRT1 especially in view of a the previous editorial in connection with stroke prevention2. I am concerned about the editorials not because they are factually incorrect but of the tone ,language and conclusions. Considering HRT paper first3 . This patient group were using HRT in standard medical practice and were generally well . If we look at the number of additional adverse events ( 8 cases of breast cancer, 7 heart attacks, 8 strokes and 8 PTE) totalling 31 per 10 000 then this gives an annualised Numbers Needed to Harm (aNNH 323). This calculation does not take in account the benefit in connection with Hip fractures and Bowel cancer. In the editorial regarding Ramipril in high risk patients4,5 to prevent stroke. These were an “at risk” group and 73% were men and 80 % had a history of coronary artery disease compared to the HRT study. Consider the annualised Numbers Needed to Treat (aNNT) to prevent the outcome of stroke (aNNT 298) and death from stroke ( aNNT 774). In both these studies therefore the aNNH (323) for HRT is similar in scale to the aNNT (298) for Ramipril. This is not reflected in the editorials. The summarising statement for HRT editorial reads “Findings of women’s health initiative need not alarm users” if this is accurate then the stroke prevention editorial summarising statement “ High risk patients should receive Ramipril irrespective of their blood pressure” surely must be inaccurate. The real answer is that both statement are misleading, with HRT not being as safe as we want to believe and Ramipril not being as effective in preventing stroke as we want to believe. This bias is understandable and reflects our medical model belief system that interventions work often even if the evidence does not support this. This should make us cautious of the role of pharmaceutical companies who trap doctors in the jaws of over stated fears of litigation and the quasi- science of their marketing machines. Chronic disease is the “Golden Goose” for the pharmaceutical industry with year on year profit which is not subject to downturn in the Global markets. Consider all the cardiovascular drugs, asthma, NSAID, epilepsy, mental heath drugs all for long-term use. These drugs represent huge vested interests in chronic disease promotion and proliferation. We as health care professions want to believe and the pharmaceutical are willing lay preachers promising salvation from disease and life eternal to our patients. It is not so. Believing is not enough when it comes health. Des Spence Competing Interests Pledge at nofreelunch.org 1. John C Stevenson and Malcolm I Whitehead Hormone replacement therapy BMJ 2002; 325: 113-114 2. Joachim Schrader and Stephan Lüders Preventing stroke BMJ 2002; 324: 687-688 3. Writing group for the Women's Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women. JAMA 2002; 288: 321-333 4. Jackie Bosch, Salim Yusuf, Janice Pogue, Peter Sleight, Eva Lonn, Badrudin Rangoonwala, Richard Davies, Jan Ostergren, and Jeff Probstfield Use of ramipril in preventing stroke: double blind randomised trial BMJ 2002; 324: 699. 5. The Heart Outcome Prevention Evaluation Study Investigators. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients N Engl J Med 2000; 342: 145-153 |
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Kevin S. Channer, consultant physician & cardiologist royal hallamshire hospital, sheffield, s10 2jf
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I was dismayed to read the editorial by Stevenson and Whitehead 1 (BMJ 2002;325:113-4) who have attempted to allay the fears of women taking hormone replacement therapy (HRT) following the latest report from the Women’s Health Initiative Study. Is it not appropriate for those writing editorials to review the literature and produce evidence based advice? As far as I can see the facts are as follows: 1. HRT causes an early excess risk of venous thromboembolism which has consistently been shown in both observational studies and in two large randomised placebo-controlled trials (table 1a). 2. HRT causes an early excess risk of cardiovascular events including death (table 1b). 3. HRT causes a later risk of breast cancer (table 1c). Although it is appropriate to discuss the type of HRT used in these trials it is not justifiable to state that this therapy is safe to use for the “short term relief of menopausal symptoms”, since women are most at risk of a vascular event in the first year of treatment. The risk may be small in absolute terms but I have never heard of a case of a woman dying of the menopause. Women – please forgive me – I am a man and a cardiologist. Sincerely, Kevin S. Channer Consultant Physician & Cardiologist Royal Hallamshire Hospital, Sheffield S10 2JF kevin.channer@sth.nhs.uk Table 1. Showing the relative risk of venous thromboembolism, cardiovascular events and breast cancer over time in studies of HRT in women. 1a. Venous thromboembolism Relative Risk (users vs non-users/placebo) Gutthann2 Davy3 HERS4 WHI5 0-6 months 2.5 Year 1 1.6 4.1 3.3 3.6 Year 2 0.6 3.2 4.1 2.3 Year 3 2.4 1.7 Year 4 1.2 2.1 1.8 1b. Coronary Heart Disease and Breast Cancer Relative risk (users vs placebo) Coronary Heart Disease Breast Cancer Relative Risk Relative Risk HERS4 WHI5 HERS4 WHI5 Year 1 1.5 1.8 0.62 Year 2 1.6 1.2 0.83 Year 3 0.9 1.1 1.73 Year 4 0.7 1.0 1.3 2.64 References: 1. Stevenson J.C., Whitehead M.I. Hormone replacement therapy. BMJ 2002;325:113-4. 2. Gutthann S.P., Rodriguez L.A.G., Castellsague J., Olliart A.D. Hormone replacement therapy and risk of venous thromboembolism : population based case – control study. BMJ 1997;314:796-800. 3. Davy E. Vessey M.P. Hawkins M.M. Carson J.L. Gough P. Marsh S. Risk of venous thromboembolism in users of hormone replacement therapy. Lancet 1996; 348: 977-80 4. Hulley S., Grady D., Bush T., Furberg C., Herrington D., Riggs B., et al. Randomised trial of oestrogen plus progestin for secondary prevention of coronary heart disease in post menopausal women. JAMA, 1998;280:6050-13. 5. Writing Group for the Women’s Health Initiative Investigators. Risk and benefits of oestrogen plus progestin in healthy post menopausal women. JAMA, 2002;288:321-33. |
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Eberhard M Greiser, Prof. (Epidemiology & Med. Statistics),Faculty of Health Sciences, Bremen University Bremen Inst. for Prevention Research & Social Medicine (BIPS), Linzer Str. 8, d-28359 Bremen,Germany, Claudia Steding, Katrin Janhsen, Klaus Giersiepen
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Dear Sir, in contrast to the editorial of Dres. Stevenson and Whitehead (1) it is our opinion that the Women's Health Initiative (WHI) results on estrogen plus progestin treatment in postmenopausal women (2) must be of great concern because of its potential public health implications. The authors themselves stress that their results on endpoints probably underestimate the true impact because they wisely analysed the data according to intention to treat. Thus they derive at the conclusion that regarding invasive breast cancer per 10.000 women treated per year 8 additional cases would arise. This, however, can only be applied to a female population that - similar to women included into the WHI trial - receive only about five years of estrogen-progestin combination drugs. We recently conducted a representative telephone survey (3) on Bremen City women which showed much longer lifetime intake in a considerable proportion of Bremen City residents (Table 1). As Fletcher and Colditz (4) in commenting on the WHI principal results paper pointed out the detrimental results probably can also be applied to estrogen-progestin combination drugs with different formulations. To appraise the public health impact it would be helpful to have a figure on risk increase per year of use. Fortunately the authors of the WHI principal results paper (1) in table 4 provided data to derive such an indicator. Using meta-analysis methods we calculated Mantel-Haenszel relative risks, respective confidence intervals and variances (5) for year 1 to 5 of the study. Summary relative risk increase per year of use was calculated applying the method proposed by Berlin and coauthors (6). Mantel-Haenszel estimates of relative risks are nearly identical to those presented in Table 4 of the WHI publication (Table 2). The calculated risk increase per year of 10.4% is consistent with annual increases observed in recent large epidemiologic studies of 7% (7), 8% (8), and 9 % (9). For the public perception of WHI results it seems much more graphic to point out that an average women, aged 65 through 69, having applied estrogen-progestin hormone therapy for more than eleven years will have her breast cancer risk more than doubled in doing so.
Table 1. Lifelong prevalence of use of estrogen-progestin combination drugs in Bremen City resident women. Telephone survey conducted May - November 2000 (2871 interviews, response 66.8%).
Table 2. Relative risk for invasive breast cancer by year of treatment with estrogen plus progestin in the Women's Health Initiative Randomized Controlled Trial, calculated in using Mantel-Haenszel estimates for relative risks and 95% confidence intervals. Risk increase was calculated using a procedure proposed by Berlin et al. (6). (Data utilized from Table 4 of the WHI principal results paper (2).)
Literature
Eberhard Greiser, M.D. Professor of Epidemiology and Biostatistics Director, Bremen Institute for Prevention Research and Social Medicine greiser{at}bips.uni-bremen.de
Claudia Steding Postgraduate student of epidemiology and public health Bremen Institute for Prevention Research and Social Medicine csteding{at}uni-bremen.de Klaus Giersiepen, M.D. Bremen State Cancer Registry Bremen Institute for Prevention Research and Social Medicine giersiep{at}bips.uni-bremen.de Katrin Janhsen Clinical pharmacist Division of Social Medicine and Pharmaco-Epidemiology Bremen Institute for Prevention Research and Social Medicine janhsen{at}bips.uni-bremen.de Address for correspondence: Prof. Dr. med. Eberhard Greiser Bremen Institute for Prevention Research and Social Medicine Center for Public Health, University of Bremen Linzer Str. 8-10 28359 Bremen, Germany greiser{at}bips.uni-bremen.de Conflict of interest: none |
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