Maturitas 42 (2002) 255 Á/258 www.elsevier.com/locate/maturitasResults from WHI and HERS II - Implications for women and the prescriber of HRT Manuel Neves-e-Castro *, Goran Samsioe, Martina Doren, Sven O Skouby ¨ ¨ On behalf of the European Menopause & Andropause Society (EMAS)1. Background 0.7 and 0.8 cases per 1,000 woman / years a figure that is easier to interpret. It would suggest that if Placebo controlled randomised clinical trials are 1000 women were treated during one year thereconsidered to be the gold standards to assess the would be less than one woman with an adversereal risks and benefits of chronic treatments. This effect.was the case with the WHI, a study aimed at the As the WHI investigators say ‘the increased riskprimary prevention of cardiovascular diseases in of breast cancer for each woman in the WHI studyhealthy postmenopausal women. who was taking the estrogen plus progestin The WHI safety committee [1,2] decided to therapy was actually very small: less than a tenthinterrupt one arm of the study because women of 1 percent per year’ . This is more realisticon the combined estrogen-progestin, at the end 5.2 than the reported relative risk increase of 26% foryears, had an increase in the relative risks for breast cancer.cardiovascular events and breast cancer, though It is reassuring that there was ‘no difference inwith a lesser risk of osteoporotic fractures and total mortality of all causes’ and it is also a verycolon cancer. However, interim reports on women important conclusion that only 2.5% of women inon estrogens alone did not show adverse CV or the estrogen plus progestin, had those healthbreast cancer crossing the predetermined safety events . Thus, ‘the absolute risk of the studyboundaries, and this part of the trial thus con- arm to an individual woman is small’ . ‘Thetinues. absolute excess risk events included in the global The order of magnitude of the relative risks is index was 19 per 10 000 person/years’ ; that is toimpressive. However, absolute risks are small per say that 1000 women would have to be treated10 000 woman / year, an abstract figure of extra- during one year in order to cause two events. Thepolation that does not reflect the actual results: at increased risk of breast cancer became apparentthe end of 5.2 years there were 7968 women in the only after the fourth year of treatment. Thesetreated group and 7608 in the placebo group.Therefore, if the absolute risks are plotted as cancers were invasive. In the protocol of the studypercentages, instead of the additional 8 strokes, 7 it is mentioned that women had to have a base lineheart attacks and 8 breast cancers per 10 000 mammography .woman / year one would have, respectively, 0.8, Another puzzling aspect of this study is the high drop out rate of 42% in the estrogen plus progestin group that, over time, has exceeded the design * Corresponding author projections. At the time of this report clinical0378-5122/02/$ - see front matter # 2002 Published by Elsevier Science Ireland Ltd.PII: S 0 3 7 8 - 5 1 2 2 ( 0 2 ) 0 0 2 1 4 - 1
256 M. Neves-e-Castro et al. / Maturitas 42 (2002) 255 Á/258gynaecologists had been unblinded to treatment in women with less than 3 live births and in thoseassignment for 3444 (40.5%) women in the estro- living alone! The observed lower event rate ingen plus progestin group and 548 (6.8%) women in smokers compared with non-smokers in the hor-the placebo group, primarily to manage persistent mone group is intriguing. There is a higher eventvaginal bleeding. During the trial 248 women in rate among users of digitalis in the hormone groupthe estrogen plus progestin group and 183 in the compared with the placebo groups . The authorsplacebo group had an hysterectomy . This is a of these re-analyses of the HERS Study concludesign of excessive dose for women between 60-69 that they did not identify any sub-groups of HERS(45.3%) and 70Á/79 (21.3%). No information is participants in which postmenopausal treatmentavailable about which of the age groups had more was clearly beneficial or harmful.vaginal bleeding. Thus this fixed excessive dose for The recommendation of WHI Committee is thatolder women does not necessarily reflect optimal continuous estrogen plus progestin should not begood clinical practice and is not followed by any used even for the primary prevention of heartresponsible gynaecologist. disease, and that they only should be used for the The findings in WHI for stroke are consistent relief of vasomotor symptoms! In a re-analysis ofwith, but somewhat more extreme than, those of HERS follow-up during 6.8 years of hormoneHERS . This is puzzling since the HERS therapy (HERS II) it was concluded that lowerparticipants where definitely sicker (CV) than rates of CHD events among women in thethose in WHI, supposed to be CV disease free. hormone group in the final years of HERS didUnlike HERS which showed no benefit or harm not persist during additional years of follow up .after 6.8 years of hormone use, WHI found moreheart disease in women taking the combinedtherapy after 5.2 years. This is a key finding 3. Clinical implicationsbecause WHI results apply to healthy womenwhile HERS involve women with heart disease . It is not an easy task to opt between results of It must be emphasized that the WHI report observational and clinical trials. High qualitystresses that the results do not necessarily apply to observational studies may extend evidence over alower dosages of those drugs, to other formula- wider population and are likely to be dominant intions of oral estrogen and progestin or to estrogens the identification of harms .and progestins administered through the transder- Let us go back to the WHI clinical trial and tomal route . the recommendations to stop its estrogen/pro- It seems that the recommendations of the WHI gestin arm.writing group are mainly focused on public rather The incidence of side effects was really very,than individual health, since they say that, even very small in terms of individual health. There is nosmall individual risks over time, and on a popula- reason to avoid postmenopause hormone medica-tion-wide basis, add up to ten’s of thousands of tion when indicated and not contra-indicated .those serious adverse health events and becomes Second, it must be stressed that the main goal isan important public health concern. Those data women’s health and not hormonal therapies. Thedescribe increased risk of an entire population, not Nurses Health Study  has shown that betweenthe increased risk for individual women . 1980 and 1994 there was a 31% reduction in CHD. Better nutrition, cessation of smoking, and hor- monal treatments in the menopause, were respon-2. Comments sible for the 18%, 13% and 9% reduction, respectively. The results reported in clinical trials are some- Third, the results of a crucial study shouldtimes difficult to interpret. For instance, in the preferably be expressed in such a way that practi-HERS Study it is difficult to explain why hormone tioners may use them for their practice to informtherapy would increase the risk of coronary events users. A very useful way is the Number Needed to
M. Neves-e-Castro et al. / Maturitas 42 (2002) 255 Á/258 257Treat (NNT) and the Number Needed to Harm healthy women. The Nurses’ Health Study and(NNH) which are respectively the reciprocals of studies from Europe, where estradiol is the com-absolute risk reduction and absolute risk increase . monly prescribed form of estrogen, suggest thatThese are expressions that are easier to extrapolate the estrogen at lower doses may confer similarinto clinical practice. benefit’’ . We are nowadays facing an extremely difficult Luckily one has nowadays an ample choice ofdilemma vis-a-vis the care of postmenopausal ` strategies and drugs (hormonal and non-hormo-women. The important issue after all is not the nal) that enable a conscientious physician to do hisimproperly named hormone replacement therapy best to restore the confidence of those women who. What is important is the best possible have sought his help.approach to preventive medicine in a mid-aged The WHI is an important study. It was meant towoman. The prescription of long-term hormonal prove the clinical effectiveness of ONE specifictreatments for osteoporosis must depend always estrogen and progestin to prevent heart disease.on a benefit/risk analysis in comparison with non- This concept failed in this specific, large group ofhormonal medications and strategies. At present, women studied. WHI does not introduce new rulesin some European countries the indication for to good clinical practice.prevention of postmenopausal osteoporosis by Given these latest additions to our overallHRT will be re-assessed according to public knowledge the policy of EMAS wil be to:statements of drug licensing authorities. It mustbe made clear that the concept of HRT does not 1) Recommend the use of any HRT to womenmean that all postmenopausal women must be with climacteric symptoms likely to impact onalways under hormonal treatments [11,12]. quality of life and to re-emphasize that topical Our main goal, as attending physicians of use of low dose vaginal estrogens can be usedpostmenopausal women, is the maintenance of by any woman carrying an indication for suchtheir health and the primary and secondary pre- therapy.vention of the diseases, which are more prevalent 2) To reassess the need of HRT after four yearsafter age 50 . of therapy and not recommend HRT for the sole purpose of preventing chronic disease, Preventing a woman from the benefits of a such as cardiovascular disease or osteoporosis sound postmenopausal hormone therapy as other alternatives are available. because of the fear of rare side effects does 3) To promote the use of additional and alter- not seem to be satisfactory Medicine. . . native non-hormonal strategies for maintain- Primum, non nocere , neither by excess nor ing health and preventing disease in symptom by abstention, as well. . . . free women of middle age and beyond.4. Conclusions and Recommendations References  Writing Group for the Women’s Health Initiative Inves- The WHI decision to stop the estrogen progestin tigators. Risks and beneﬁts of estrogen plus progestin inarm does not necessarily change a wise clinician’s healthy postmenopausal women. JAMA 2002;288(3):321 Á/decision as to the best clinical care of a post- 33.menopausal woman. However, we all have learnt  Fletcher WS, Colditz GA. Failure of estrogen plusnow to be ever more cautious in discussing risks progestin therapy for prevention. (Editorial) JAMAand benefits of estrogen and progestin treatment. 2002;288(3):366 Á/8.  Roussouw J. Release of the Results of the Estrogen PlusMore recent epidemiological studies continue to Progestin Trial of the Women’s Health Initiative: Findingssupply evidence that long-term postmenopausal and Implication. Press Conference Remarks July 9, 2002.hormone therapy may reduce the risk for CAD in http://www.nhlbi.nih.gov/whi/hrtupd/roussouw.htm
258 M. Neves-e-Castro et al. / Maturitas 42 (2002) 255 Á/258 New Facts About: Estrogen/Progestin Hormone Therapy.  Hu FB, Grodstein F, et al. Trends in the incidence of WHI HRT Update Newsletter, July 2002. http://nhlbi. coronary heart disease and changes in diet and lifestyle in nih.gov/whi/hrtupd/ep_facts.htm women. NEJM 2000;343:530 Á/7. The Women’s Health Initiative Study Group. Design of  Neves-e-Castro M. Is there a menopausal medicine? The the Women’s Health Initiative Clinical trial and observa- past, the present and the future. Maturitas 2002 (in press). tional Study. Controlled Clin Trials 1998;19:61 Á/109.  Neves-e-Castro M. The Queen ... is naked! Maturitas Furberg CD, et al. Subgroup Interactions in the Heart and 2001;38:235 Á/7. Estrogen/Progestin Replacement Study. Circulation  Neves-e-Castro M. Imaginary women. Maturitas 2002;105:917 Á/22. 2001;40:5 Á/15. Grady D. Cardiovascular disease outcomes during 6.8  Neves-e-Castro M. When hormone replacement therapy is years of hormone therapy. heart and estrogen/progestin not possible. The Management of the Menopause. The Millennium Review, Parthenon 2000:91 Á/102. replacement study follow-up (HERS II). JAMA  Neves-e-Castro M. Where are we now? Menopause: 2002;288(1):49 Á/57. Hormones and Cancer. Edited by M. Neves-e-Castro Barton S. Which clinical studies provide the best evidence? and B.G. Wren. Parthenon 2002: 141 Á/5. The best RCT still trumps the best observational study.  Hu FB, Grodstein F. Postmenopausal hormone therapy BMJ 2000:321:255 Á/6. and the risk of cardiovascular disease: the epidemiologic evidence. Am J Cardiol 2002; 90(1) Supl.1:F26 Á/9.