Research and Practice in Thrombosis and Haemostasis | 2021
Does publication bias explain the divergent findings on menopausal hormone therapy and cardioprotection in the literature?
Abstract
As women traverse the menopause transition, they lose the ability to produce estradiol, and their risk of developing cardiovascular disease (CVD) increases.1 The use of menopausal hormone therapy (HT) has been viewed as a way to counteract ovarian aging and the accompanying elevation in CVD risk. Initial observational studies of HT use in the 1980s and 1990s strongly supported this argument. In data from the Nurses’ Health Study among 48 470 postmenopausal women (30– 63 years old) followed for 10 years, a reduction in the incidence of coronary heart disease (CHD) as well as in cardiovascular disease (CVD) mortality, was observed with current use of HT.2 Of 16 prospective studies on this subject, 15 found decreased relative risks of CHD among women using HT compared to nonusers,3 supporting a protective association with estrogen therapy. These favorable findings led to an endorsement of HT use for cardiovascular health, even appearing in some clinical guidelines.4 The findings also inspired two landmark doubleblind and placebocontrolled randomized clinical trials (RCTs) to test HT use (conjugated equine estrogens [CEEs]/with and without medroxyprogesterone acetate) for primary (Women’s Health Initiative [WHI])5 and secondary prevention (Heart and Estrogen/Progestin Replacement Study [HERS])6 of CVD in the 1990s. Surprisingly for the medical and research communities, both trials did not confirm the positive findings from previous observational studies,2,3 casting doubt on a cardioprotective effect and even suggesting a harmful effect of HT use for primary or secondary prevention of CVD. Since that time, researchers have actively sought answers to explain the discrepancy between positive findings of observational studies and the negative outcome of the WHI/HERS trials. In this issue of Research and Practice in Thrombosis and Haemostasis (RPTH), Berntsen et al7 shift the focus of this comparison from observational studies in humans to animal studies. Most animal studies testing effects of estrogens on atherosclerosis and vascular disease had shown beneficial effects, and these positive results further bolstered a case for HT and cardioprotection. Berntsen et al conducted an elegant systematic review and metaanalysis of published animal studies comparing estradiol and its natural metabolites or CEE, with controls for effects on measures of atherosclerosis. The authors assessed whether confirmation and/or publication bias could explain the discrepancy between the favorable findings for HT in animal studies versus the neutral or adverse effects found in major RCTs. Confirmation bias refers to the seeking or interpreting of evidence in ways that are partial to existing beliefs, expectations, or a hypothesis in hand.8 The authors hypothesized that this bias may have resulted in interpreting findings from animal studies on estrogen use differently before versus after the landmark WHI publication.5 Contrary to the authors’ hypothesis, no evidence was found of a change in researchers’ interpretations of their own findings before versus after WHI. Strikingly, 75% (95% confidence interval [CI], 67%81%) of animal studies conducted before WHI concluded that estrogens had a protective effect on atherosclerosis compared with 78% (95% CI, 71%83%) of animal studies conducted after WHI.7 This reported finding is strong evidence that experimental animal research has been consistent in showing a protective effect