The truth about study outcomes that misled the public and health care practitioners.
Designed in the early 1990s, the Women’s Health Initiative (WHI) hormone replacement therapy (HRT) trial was built upon findings in a variety of observational studies that consistently suggested HRT could prevent major age-related diseases, especially cardiovascular disease. Those prior studies largely reflected initiation of HRT in newly menopausal women and long-term use, primarily of high-dose unopposed oral estrogen (typically conjugated equine estrogens 1.25 mg daily) as used in the 1960s and 1970s. Combined HRT came into wide use in the 1980s following the rise in rates of endometrial carcinoma in the mid-1970s associated with the early unopposed regimens. Observational studies published in the 1980s that reported outcomes associated with earlier regimens suggested that HRT might reduce the risk of coronary heart disease (CHD) events – the leading cause of death in women living in developed nations – by approximately 50%1–4 Stampfer MJ, Willett WC, Colditz GA, et al.
The critical problem with the CEE + MPA paper was the failure to clearly acknowledge that the WHI was not designed to assess outcomes, particularly the stipulated primary outcome of CHD, in younger menopausal women who were the vast majority of ‘real world’ patients using HRT. It did not acknowledge that only 30% of participants were <60 years old, with just 12% aged 50–54. Instead, it inappropriately generalized the findings in a predominantly older population that was not representative of typical users to the population of typical users.
That good science became distorted and ultimately caused substantial and ongoing harm to women for whom appropriate and beneficial treatment was either stopped or never started. Key faults have included: failure to properly identify the study goals and population characteristics in presenting and interpreting the results; inappropriately generalizing the findings to a key sub-group – newly menopausal women – that was not adequately represented; inappropriately generalizing the findings from specific medications to an entire class; failure to put the findings in the context of existing knowledge (taking the position that the prior studies were simply wrong); favoring publicity, fear and sensationalism over science; and departing from protocol – focusing on unadjusted results, while avoiding planned analyses with proper adjustments and better statistical power.
The key and reassuring fact regarding the breast cancer outcomes emerged relatively soon after the initial publications. It has been largely ignored in reporting and interpreting the study. This is the observation that the apparent increase in the breast cancer rate in the CEE + MPA group was due to an unexplained lower rate in the women randomized to placebo who had previously used HRT, NOT an increased rate in women randomized to CEE + MPA. Among women with no prior use of HRT before entering the WHI, there was no difference in breast cancer rates over time between the women assigned to placebo or CEE + MPA18 Anderson GL, Chlebowski RT, Rossouw JE, et al. Prior hormone therapy and breast cancer risk in the Women’s Health Initiative randomized trial of estrogen plus progestin. Maturitas 2006;55:103–15[CrossRef], [PubMed], [Web of Science ®], [Google Scholar]. This HRT-naïve subgroup likely represents the best population for assessing HRT effects. The breast cancer trend in women with prior use of HRT who were assigned to active CEE + MPA was similar to that in the active and placebo HRT-naïve groups. In contrast, the breast cancer rate in women assigned to placebo who had previously used HRT was much lower than the rates in all three other groups. That unexpected and unexplained low rate, different from the rate in the other placebo group, was the basis for the apparent increased hazard.
Where does that leave us in 2016? It is time to get past the misinformation and hysteria generated by the highly irregular circumstances of the WHI and stop denying potential benefits (control of vasomotor symptoms, prevention of fractures, prevention of CHD) to women who have indications and may be helped. HRT is appropriate for symptomatic women within 10 years of menopause who have no major contraindication. Good evidence from over 50 years of observational studies and clinical trials suggests that the benefits outweigh the risks for most women when started early. The International Menopause Society has recently published updated recommendations for HRT in a new format that highlights key messages and clinical pearls33 Baber RJ, Panay N, Fenton A, for the IMS Writing Group. 2016 IMS Recommendations on women’s midlife health and menopause hormone therapy. Climacteric 2016;19:109–50[Taylor & Francis Online], [Web of Science ®], [Google Scholar]. It is a well documented and authoritative guide for contemporary clinical practice.
Langer R.D. April 2017. The evidence base for HRT: what can we believe? Climacteric. 20(2):91-96. doi: 10.1080/13697137.2017.1280251. Epub 2017 Mar 10.