News and views Post Reproductive Health 2014, Vol. 20(4) 129–131 ! The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/2053369114558778 prh.sagepub.com

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A huge return on investment for the WHI The cost of the combined therapy arm of the Women’s Health Initiative (WHI) trial was an eye-watering $260 million dollars when calculated at 2012 rates, but ‘the real’ return to the US economy was an even more staggering $37 billion, according to a recent health outcomes modelling study.1 ‘The E þ P trial made highvalue use of public funds with a substantial return on investment’, said the investigators, some of whom included usual suspects from the original trial of 2002 and from the trial’s sponsors at the National Institutes of Health (NIH). Calculated over a study period from 2003 to 2012, the outcome of the trial was found to represent an economic return of $140 for every dollar spent – and a persuasive case for ‘for large, prospective trials with high potential for public health effects’. ‘Americans should be pleased to see that their investment in NIH continues to provide such a strong return to their health and the economy’, added the NIH Director in a press statement. The model for the study included disease incidence, direct medical expenditure, quality-adjusted life years and net economic return in approximately 39.1 million women eligible for combined hormone therapy between 2003 and 2012 in either a ‘WHI scenario’ or a parallel universe of ‘no-WHI scenario’. With this distinction and an estimation of who would (and would not have) used combined hormone therapy, it was projected that the WHI scenario resulted in 4.3 million fewer users of combined therapy than the no-WHI scenario, 126,000 fewer breast cancer cases, 76,000 fewer cardiovascular events, 145,000 more quality-adjusted life years, but 263,000 more fractures and 15,000 more colorectal cancers. Lead study author Roth said that the quality of life, mortality and cost impacts of more osteoporotic fractures (and colorectal cancers) were more than offset by the decreases in breast cancers, cardiovascular disease and venous thromboembolism. Resulting expenditure savings were thus put at $35.2 billion (which included the savings on drug costs) and a net economic return $37.1 billion. The original budget for the WHI, according to a 1992 press release from the NIH, was $625 million, with a duration of 15 years and the inclusion of

150,000 women.2 It was billed as ‘the largest coordinated study of women’s health ever undertaken’; in the event there were 16,608 women with an intact uterus in the combined therapy study, and 10,739 women without a uterus in the estrogen-alone trial. ‘The motivation for the first WHI trial was to see if we could prevent heart disease’, said Garnet Anderson, an investigator from the original WHI study. That’s why we did it - the economics never occurred to me. But what these findings underscore is the significant role clinical trials play in science and the importance of continuing to find ways to strategically invest public research funds to maximize value to society.

The only self-confessed ‘limitation’ of note in the published study is a lack of cost evaluation after 2012, with no mention of symptom relief or of cardiovascular benefits in recently menopausal women. And of course, to accept this cost-benefit analysis (which anyway seems dogged by conflicts of interest) one has necessarily to accept the hazard ratios of the original trial. Yet, no concession appears to have been made to the WHI’s revisit to its own cardiovascular data, or to the several studies which re-examined the WHI findings on coronary heart disease (CHD) and breast cancer. A secondary analysis by the WHI of combined therapy’s effects on CHD proposed that women who began therapy within the first 10 years following the menopause actually reduced their risk of CHD (a hazard ratio of 0.76).3 Similarly, an application of epidemiological ‘causal principles’ to the WHI’s breast cancer findings by Shapiro et al.4 concluded that the WHI had failed to establish clearly that combined hormone therapy does actually increase the risk of breast cancer. Yet, these doubts and modifications remain apparently ignored in this self-serving cost-benefit analysis. 1. Roth JA, Etzioni R, Waters TM, et al. Economic return from the Women’s Health Initiative Estrogen Plus Progestin clinical trial: a modeling study. Ann Intern Med 2014; 160: 594–602. 2. See http://www.nhlbi.nih.gov/whi/pr_92-10-2.pdf (accessed 23 October 2014).

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3. Rossouw JE, Prentice RL, Manson JE, et al. Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause. JAMA 2007; 297: 1465–1477. 4. Shapiro S, Farmer RD, Mueck AO, et al. Does hormone replacement therapy cause breast cancer? An application of causal principles to three studies: part 2. The Women’s Health Initiative: estrogen plus progestogen. J Fam Plann Reprod Health Care 2011; 37: 103–109.

Two large RCTs fail to demonstrate any benefit of bisphosphonates in breast cancer There has been some evidence that bisphosphonates, commonly used to treat osteoporosis, may also offer some protection against breast cancer. For example, the ABCSG-12 trial found that addition of zoledronic acid to adjuvant endocrine therapy (goserelin and tamoxifen or goserelin and anastrozole) improved disease-free survival in premenopausal patients with estrogen-responsive early breast cancer.1 However, a new analysis of data from two large randomised clinical trials (RCT) has found that three to four years of treatment with bisphosphonates to improve bone density is not linked to any reduced risk of invasive postmenopausal breast cancer.2 ‘The discrepancy between our results and the reports of associations in observational studies may be an example of indication bias and illustrates the limitation and hazard of drawing conclusions about treatment effects from observational studies (even those that are very well done)’, the investigators reported. They compared the rates of breast cancer in the bisphosphonate and placebo groups in two randomised trials: the Fracture Intervention Trial (FIT), which randomly assigned 6459 women (ages 55–81 years) to alendronate or placebo with an average follow-up of 3.8 years; and the Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly-Pivotal Fracture Trial (HORIZON-PFT), which randomly assigned 7765 women (ages 65 to 89 years) to annual intravenous zoledronic acid or placebo with an average follow-up of 2.8 years. Their analysis found no significant difference in breast cancer incidence between the bisphosphonate and placebo groups. In FIT, the breast cancer rate was 1.5% in the placebo group and 1.8% in the alendronate group; in HORIZON-PFT, the rate was 0.8% in the placebo group and 0.9% in the zoledronic acid group. There also was no significant difference when data from the two trials were combined. An editorial accompanying the report once again highlights the dangers of basing practice on

non-randomised studies.3 Although a recent Cochrane review found little evidence that the results of observational studies and RCTs systematically disagreed, this editorial insists that new therapies must ideally be evaluated in RCTs. 1. Gnant M, Mlineritsch B, Schippinger W, et al. ABCSG-12 Trial Investigators. Endocrine therapy plus zoledronic acid in premenopausal breast cancer. N Engl J Med 2009; 360: 679–691. 2. Hue TF, Cummings SR, Cauley JA, et al. Effect of bisphosphonate use on risk of postmenopausal breast cancer: results from the randomized clinical trials of alendronate and zoledronic acid. JAMA Intern Med 2014; 174: 1550–1557. 3. Ross JS. Randomized clinical trials and observational studies are more often alike than unlike. JAMA Intern Med 2014; 174: 1557.

Hormone therapy in early menopause does not slow progression of atherosclerosis It was always hoped that the Kronos Early Estrogen Prevention Study (KEEPS) would provide an everyday balance to the Women’s Health Initiative (WHI) in its assessment of cardiovascular risk associated with hormone therapy started during the menopause transition. Women in the WHI were on average 63 years old (20% of them aged 70–79 years) and 12 years beyond the menopause; KEEPS subjects were ‘younger, healthier, and within three years of menopause’, thus matching more closely the demographics of women using hormones and in the earlier observational studies. The results of the four-year trial of low-dose oral or transdermal estrogen and cyclic monthly progesterone were presented at the 2012 meeting of the North American Menopause Society and confirmed that treatment relieves many of the symptoms of the menopause and improves mood and bone density. However, while there was some evidence of improvement in several markers of cardiovascular risk, the between-group differences were not statistically significant. Now, a further study in this same population using non-invasive vascular imaging has still failed to find any evidence that hormone therapy slows the progression of atherosclerosis.1 Increases in mean carotid intima-media thickness (of 0.007 mm/year) were similar across groups – as were the percentages of subjects in whom coronary artery calcium score increased. ‘We were disappointed because earlier research, especially by Howard Hodis, saw a deceleration in atherosclerosis progression with estrogen’, said lead investigator Mitchell Harman. Former WHI investigator

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JoAnn Manson, who was not involved in the KEEPS trial, however, said that despite the results ‘hormone therapy initiated early in menopause appears to have a favorable balance of risks and benefits with a substantial improvement in vasomotor symptoms and quality of life and improvement in a number of biomarkers’. 1. Harman SM, Black DM, Naftolin F, et al. Arterial imaging outcomes and cardiovascular risk factors in recently menopausal women. Ann Intern Med 2014; 161: 249–260.

More guidelines for the care of midlife women Just weeks after the International Menopause Society (IMS) introduced its menopause toolkit for GPs (already said to be the most popular download ever from the IMS’s journal Climacteric), the North American Menopause Society has published its first ‘comprehensive set of evidence-based recommendations for the care of midlife women’.1,2 The 25-page report was compiled by an editorial panel of nine US experts and many further contributors. ‘This very practical publication includes key points and recommendations for care on more than 50 important topics, including such key issues as vasomotor symptoms, osteoporosis and genitourinary syndrome of menopause’, said Margery Gass, executive director of National Academy of Medical Sciences (NAMS). Additionally covered are sexual function, cognition, cardiovascular health, thyroid disease and cancers. Further sections review basic physiology, counselling, screening tests and complementary and alternative therapies. All recommendations are graded for their level of evidence. The recommendations are freely available on the NAMS website.3 1. Jane FM and Davis SR. A practitioner’s toolkit for managing the menopause. Climacteric 2014; 17: 564–579. 2. Shifren JL and Gass MLS. The North American Menopause Society recommendations for clinical care of midlife women. Menopause 2014; 21: 1038–1062. 3. See http://www.menopause.org/docs/default-source/2014/ nams-recomm-for-clinical-care (accessed 23 October 2014).

AMH in the prediction of age at menopause Anti-Mu¨llerian hormone (AMH) has emerged as the most striking reproductive hormone of the past decade. As a marker of ovarian reserve, AMH has been shown to predict response to ovarian stimulation (though not yet pregnancy) in in vitro fertilisation and – with somewhat less reliability so far – the individual age at which the menopause might occur. This latter prediction depends largely on the observation that AMH levels tend to become undetectable around five years before the menopause. Endocrine and other changes likely to predict early subfertility may be an indication for oocyte freezing (or early natural conception) and thus a prelude to the primary prevention of premature infertility. Four models have so far been presented for the prediction of menopausal age with serum AMH, and two of them have now been validated in a ‘cross-validation’ study.1 The two models came from two cohorts, the Scheffer, van Rooij, de Vet cohort and the Tehran Lipid and Glucose Study (TLGS) cohort. The former is based on three longitudinal studies performed in the Netherlands in which AMH was determined at baseline in 257 normo-ovulatory women aged between 21 and 46 years and cycle status around 11 years later. The TLGS cohort was based on the Tehran Lipid and Glucose Study from which AMH was measured at baseline in 266 eligible women and cycle status assessed six years later. This latest study aimed to cross-validate and compare these two models of predicting menopausal age, using AMH and age as the two main variables. A complex statistical analysis showed that, despite some discrepancies between the two models, both were able to discriminate well between those who entered the menopause early or late during follow-up. The results, say the investigators, thus provide further evidence that the prediction of age at menopause with AMH ‘has definite potential’. And they reaffirm the hope that such predictions ‘may pave the road to individualized prevention of primary age-related infertility and menopauserelated conditions’. 1. Ramezani TF, Dolleman M, Van Disseldorp J, et al. Predicting menopausal age with anti-Mu¨llerian hormone: a cross-validation study of two existing models. Climacteric 2014; 17: 583–590.

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A huge return on investment for the WHI.

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