Friis Berntsen Christopher, Rootwelt Pernille, Dahm Anders Erik Astrup
Department of Medicine Sykehuset Innlandet Hospital Trust Gjøvik Norway.
Institute for Health and Society University of Oslo Oslo Norway.
Res Pract Thromb Haemost. 2021 May 5;5(4):e12507. doi: 10.1002/rth2.12507. eCollection 2021 May.
Randomized controlled trials on menopausal hormone therapy in humans have not confirmed the benefit of estrogens on cardiovascular disease found in animal studies. Flawed methodology or publication bias in animal studies may explain the dicrepancy.
The aim of this study was to investigate whether publication of the randomized controlled trials Heart and Estrogen/Progestin Replacement Study and Women's Health Initiative influenced study authors' assessment of research findings (confirmation bias) as well as to investigate publication bias and small-study effects in animal studies of estrogen effects on atherosclerosis.
The data source for this study was PubMed from inception to 2018. We selected animal studies with cardiovascular outcomes comparing 17-β-estradiol, its natural metabolites, or conjugated equine estrogen with control. Qualitative data were extracted on authors' conclusions about estrogen effects on cardiovascular disease, as well as quantitative data for atherosclerosis outcomes. Fixed- and random-effects meta-analyses were used. Publication bias/small-study effects were assessed using funnel plots and Egger's regression. Trim-and-fill plots and extrapolation from Egger's regression were used to adjust for publication bias. The main outcomes and measures were the primary study authors' interpretation of their own results, and estrogen effects on cardiovascular disease in general before and after publication of the Women's health Initiative study (2003). The effects of estrogens on atherosclerosis were measured as standardized mean difference between intervention and control.
Of 1925 studies retrieved, 360 were eligible for analyses. Study-specific statements concluded that estrogens were protective against cardiovascular disease in 75% of studies before 2003 and 78% after, but the percentage of general statements about estrogens being cardioprotective changed from 70% to 40%. Meta-analyses showed less atherosclerosis in estrogen-treated animals. Extremely skewed funnel plots and < .01 in Egger's regression suggested publication bias and/or exaggerated effects in small studies, which was more pronounced after 2002. There was substantial heterogeneity of effects ( = 68%-86%) overall and in all subgroups except cynomolgus monkeys ( = 9%), the only animal subgroup without clear bias. Adjusting for publication bias, overall estimates of estrogen effects on atherosclerosis were close to null effect.
We found substantial evidence of publication bias but not of confirmation bias. Publication bias and flawed small studies may partly explain why findings differ between animal studies and clinical trials on the effect of estrogens on cardiovascular disease.
关于人类更年期激素疗法的随机对照试验尚未证实动物研究中发现的雌激素对心血管疾病的益处。动物研究中存在的方法缺陷或发表偏倚可能解释了这种差异。
本研究旨在调查随机对照试验《心脏与雌激素/孕激素替代研究》和《妇女健康倡议》的发表是否影响研究作者对研究结果的评估（确认偏倚），以及调查雌激素对动脉粥样硬化影响的动物研究中的发表偏倚和小研究效应。
本研究的数据来源为自创建至2018年的PubMed。我们选择了比较17-β-雌二醇、其天然代谢产物或结合马雌激素与对照组的具有心血管结局的动物研究。提取了关于作者对雌激素对心血管疾病影响的结论的定性数据，以及动脉粥样硬化结局的定量数据。采用固定效应和随机效应荟萃分析。使用漏斗图和Egger回归评估发表偏倚/小研究效应。使用修剪填充图和Egger回归外推法调整发表偏倚。主要结局和测量指标为主要研究作者对其自身结果的解释，以及《妇女健康倡议》研究（2003年）发表前后雌激素对心血管疾病的总体影响。雌激素对动脉粥样硬化的影响以干预组与对照组之间的标准化均数差来衡量。
在检索到的1925项研究中，360项符合分析条件。研究特异性陈述得出结论，在2003年之前，75%的研究表明雌激素对心血管疾病具有保护作用，之后这一比例为78%，但关于雌激素具有心脏保护作用的总体陈述比例从70%降至40%。荟萃分析显示，接受雌激素治疗的动物动脉粥样硬化程度较轻。极度不对称的漏斗图和Egger回归中P<0.01表明存在发表偏倚和/或小研究中的效应夸大，2002年之后更为明显。总体以及除食蟹猴外的所有亚组（I²=9%，是唯一没有明显偏倚的动物亚组）均存在显著的效应异质性（I²=68%-86%）。调整发表偏倚后，雌激素对动脉粥样硬化影响的总体估计接近无效效应。
我们发现了大量发表偏倚的证据，但未发现确认偏倚的证据。发表偏倚和有缺陷的小研究可能部分解释了为什么动物研究和雌激素对心血管疾病影响的临床试验结果存在差异。
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