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Rapid Responses: Rapid Responses published:
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HRT and coronary artery disease
- Ellen C G Grant (27 February 2004)
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Suppression of research findings is unethical
- Hazel Thornton (27 February 2004)
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The Alice and Wonderland World of Hormones
- Pepi Granat (2 March 2004)
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On-line ABPI Register Lists HRT Trials
- Richard S Tiner (18 March 2004)
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Ellen C G Grant, physician and medical gynaecologist 20 Coombe Ridings, Kingston-upon-Thames, Surrey, KT2 7JU
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In 1985 the claim of the nurses’ study authors, that postmenopausal oestrogen use reduced the risk coronary artery disease, conflicted with the results of the Framingham study.1,2 In the latter study women aged 50 to 83 using oestrogens had 50% more risk of heart disease and twice as much cerebrovascular disease than non-users. The nurses were aged 30 to 55 when enrolled and those taking oestrogen were five times more likely to have had hysterectomies and twice as likely to have used oestrogen/progesterone contraceptives than non- oestrogen users. At each two year survey women who had already got coronary artery disease were excluded from further follow-up because they might alter their pattern of hormone use. There was no reduction in total mortality when women with cancer at the base-line were eliminated.1 By1993 only 9% of the nurses were current HRT takers but 43% were taking vitamins. Nine out of ten women did not believe that HRT was beneficial.3 The epidemiology of hormone use is particularly unreliable because few women have never been given hormones at some time or other. Even randomised trials do not have clean never user groups and can underestimate risks and therefore claim non-existent benefits. 1 Stampfer MJ, Willett WC, Colditz GA, et al. A prospective study of postmenopausal estrogen therapy and coronary heart disease. N Eng J Med 1985: 313:1044-49. 2 Wilson PWF, Garrison RG, Castelli WP. Postmenopausal estrogen use, cigarette smoking and cardiovascular morbidity in women over 50. The Framingham Study. NEngJMed 1985 ;313:1038-43. 3 Stampher MJ, Colditz GA. Estrogen replacement therapy and coronary heart disease: a quantitative assessment of the epidemiologic evidence. Prev Med 1991 ;20:47-63. Competing interests: None declared |
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Hazel Thornton, Honorary Visiting Fellow, Department of Health Sciences, University of Leicester "Saionara", 31 Regent Street, Rowhedge, Colchester.
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"Many excellent notions or experiments, by sober and honest men, are suppressed." Robert Boyle. 1661 Little has changed, it seems.[1] This report of hidden, unpublished drug company data about HRT is depressingly similar to the SEROXAT anti- depressant drug scandal, where GlaxoSmithKline "managed" (i.e. held back) data from clinical trials internally within the company "in order to minimise any potential negative commercial impact." [2] Public exposure of this scandal on the BBCC "Panorama" programme was made possible by researchers working closely together with patients and public. The researchers` report [3] also compared adverse drug reaction reports from professionals with those of users. Analysis of professional reports was made possible through negotiated access to `Yellow Card` reports from the Medicine and Healthcare Products Agency and Committee on Safety of Medicines: probably the first such analysis of the scheme. The users` analysis was from 1374 e-mails sent in response to the "Panorama" programme. The programme also received 67,000 calls. This successful exposure demonstrated the important active role that public and patients can play in partnership with professional researchers in producing evidence about a treatment`s harms and benefits. Evidence is incomplete unless effects on quality of life are included. It is time clinician-researchers became equally alert to the motivations of drug companies and the pernicious effects of conflicting interests. Over a decade ago we were told that under-reporting of research is unethical and constitutes scientific misconduct. [4] For too long, obtaining evidence in randomised controlled trials about side-effects was deemed an optional extra. Even when included in a trial protocol, data are not always comprehensively gathered or reported. [5] This raises questions about the degree of open-ness in clinician/pharmaceutical research partnerships. [1] Klim McPherson, Elina Hemminki. Synthesising licensing data to assess drug safety. BMJ 2004; 328:518-20 [2] bmj.com UK Health News. Company `held back` data on Seroxat for children. 3rd February 2004. Source: The Guardian. [3] Charles Medawar, Andrew Herxheimer. A comparison of adverse drug reaction reports from professionals and users, relating to risk of dependence and suicidal behaviour. International Journal of Risk and Safety of Medicine. 2003/4; 16:5-19 [4] Chalmers I. Under-reporting research is scientific misconduct. JAMA 1990; 263:1405-1408 [5] Hazel Thornton. Questions about anastrozole for early breast cancer. Lancet 2002;360:1890 Competing interests: None declared |
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Pepi Granat, Private Family Practice and Clinical Professor of Family Medicine, voluntary 7800 Red Road, Suite202; South Miami, FL, 33143 USA
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The Alice in Wonderland world of hormones gets curiouser and curiouser. Nothing is as peculiar as double-blind fascism and medicine-by -sound-byte reigning, like the Queen of Hearts. The comments on periodontal disease (seen elsewhere in rapid responses) can go further: periodontal disease may be a heart disease predictor and is clearly improved with estrogen. Recently, since the (unwarranted) influence of WHI (Women's Health Initiative) and HERS (Heart and Estrogen Replacement Study), and until Hodis’, et al.’s insightful discussion in the New England Journal of Medicine it was “off with her head” for intrepids advocating individualized use of estrogen at onset of menopause for -- among other benefits -- preventing atherosclerosis. (The HERS study itself, later showing 35% less new-onset diabetes supports this; diabetes is a coronary artery disease equivalent). Editorialist Bailar opines, “Curiously, Hodis, et al. seem reluctant to accept their own results at face value.” He misreads Hodis’ credible perspective. Herrington & Howard cite flaws in large studies, favoring tailored, eventually molecular, individualization. They accede that “… in physiology averages give nothing real." From the Rabbit Hole crawl muddied but perspicacious physician-clinicians weighing disparate evidence. With tongue in cheek and teeth preserved (unless estrogen-deprived periodontal disease, another CAD equivalent ) we seek the toothless grin of the Cheshire cat with Alice as she ages, through the looking glass, until pivotal pieces of the puzzle prove Hodis et al.’s point. References: 1 Lewis Carroll. Alice's Adventures in Wonderland and Through the Looking-Glass, by Lewis Carroll, John Tenniel (Illustrator) (Mass Market Paperback), Dec. 2002. 2 Hodis HN, Mack WJ, Azen SP et al. Hormone therapy and the progression of coronary-artery Atherosclerosis in Postmenopausal Women N Engl J Med 2003;349:535-545. 3 Bailar J.Hormone-replacement therapy and cardiovascular disease N Engl J Med 2003;349:521-522 4 Herrington DM, Howard TD. From presumed benefit to potential harm — Hormone therapy and heart disease N Engl J Med 2003;349:519-521 5 Krall EA, Dawson-Hughes B. et al. Postmenopausal estrogen replacement and tooth retention. Am J Med 1997;102:536–42. 6 Madianos PN, Bobetsis GA et al.. Is periodontitis associated with an increased risk of coronary heart disease and preterm and/or low birth weight births? J Clin Periodontol. 2002;29 Suppl 3:22-36. Pepi Granat, MD Private Family Practice Clinical Professor of Family Medicine, voluntary University of Miami School of Medicine, Dept. Family Medicine and Community Health e-mail: pgranat@pol.net Competing interests: I have written the chapter on Menopause in Robert Taylor's Textbook of Family Medicine; I was formerly on Speaker's Bureau for Wyeth AFTER having given independent talks on estrogen and lipid and cardiovascular effects |
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Richard S Tiner, Medical Director The Association of the British Pharmaceutical Industry (ABPI), 12 Whitehall, London SW1A 2DY
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Dear Sir McPherson and Hemminki make a number of interesting points in their article “Synthesising licensing data to assess drug safety” , some important but some erroneous. The Association of the British Pharmaceutical Industry (ABPI) supports the retrospective registration of phase III trials involving UK patients when used in an application for a marketing authorisation. Indeed the ABPI launched its clinical trial register on 6 May 2003 (http://www.cmrinteract.com/clintrial) and a search on 11 March 2004 produced nine HRT trials. In registering trials, companies commit to considering reasonable requests for further information on the trial and so we would suggest that in future McPherson and Hemminki and other researchers check the website when seeking pharmaceutical industry sponsored trials. In the summary points section of the paper, there are two statements relating to adverse events. Under ICH GCP which was published and adapted by industry in January 1997, the requirement for reporting of adverse events is clear. This is now to be strengthened from 1st May 2004 through the implementation of the Clinical Trials Directive (2001/20/ec) in UK law. The reporting of serious adverse reactions in clinical trials will be a legal requirement for all investigators and they will be entered into a central European database. McPherson and Hemminki imply that there was promotion of an unlicensed indication with HRT ie the prevention of coronary heart disease. Such promotion by pharmaceutical companies in the UK is illegal and would be investigated either by the MHRA or the Prescription Medicines Code of Practice Authority. It is possible that discussions might have promoted such use but not at the instigation of companies. McPherson and Hemminki introduce the issue of compliance bias and indeed this might have been a factor but it is also well known that patients are not good compliers with medication and often take their medicines haphazardly. I suggest that compliance bias may not be as important as stated. Finally I return to the register of clinical trials. Clearly further information would have been available by approaching registering companies directly but an approach to the MHRA would have led to the relevant companies being contacted for permission to release information and these matters would have been considered on a case by case basis. Therefore it might have been more appropriate for McPherson, a member of the CSM, directly to approach the MHRA rather than rely on a personal communication from Michael Rawlins who retired as chairman of the CSM a few years ago. Yours sincerely Dr Richard Tiner
Competing interests: Medical Director of The Association of the British Pharmaceutical Industry (ABPI), 12 Whitehall, London SW1A 2DY |
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