Causal Models for CVD Use by Aspirin and Vitamin E in the Women's Health Study

描述（由申请人提供）：最近来自妇女健康研究（WHS）的随机试验数据表明，低剂量阿司匹林对主要心血管疾病（CVD）的主要终点（包括MI、中风和CVD死亡）没有总体影响。这与先前试验的荟萃分析形成对比，主要是男性，显示冠心病减少了28%。这些差异是否是由于性别或剂量造成的，仍没有答案。虽然需要额外的试验数据来充分解决这个问题，但WHS数据可用于确定研究中不同的使用是否是未来CVD事件的决定因素。我们建议使用最先进的统计方法来估计试验期间实际使用阿司匹林的因果关系，以确定实际使用是否更能预测后期CVD，以及使用的实际剂量是否对CVD有更大的影响。此外，我们将使用更新的时变协变量，以检查它们是否使用类似的方法修改试验期间实际使用阿司匹林的效果。虽然WHS中维生素E干预的数据与先前的无效试验数据更一致，但我们发现CVD死亡率的次要终点降低，以及年龄的影响。然而，这些数据中可能存在中间事件的混淆，这可能会扭曲随机分析和观察性分析的估计值。因此，我们将应用相同的因果关系方法来确定在调整随时间变化的协变量后，实际维生素E使用或剂量是否对CVD的发展有影响，并探索维生素E影响的改变。2002年，预防服务工作组（英语：Preventive Services Task Force）提出一级预防建议，强烈建议临床医生考虑对所有冠心病风险增加的成年人（包括绝经后妇女）进行阿司匹林化学预防。因此，阿司匹林对女性的真实影响以及不同剂量的影响具有重大的公共卫生相关性。对于维生素E，来自WHS的数据支持目前的指南，该指南指出使用维生素E并不能减少CVD。然而，心血管疾病死亡风险降低的结果，以及年龄的影响，应进一步探讨，以澄清公共卫生信息。

DESCRIPTION (provided by applicant): Recent randomized trial data from the Women's Health Study (WHS) demonstrated no overall effect of low dose aspirin on the primary endpoint of major cardiovascular disease (CVD), including MI, stroke, and CVD death. This contrasts with a meta-analysis of previous trials, mostly in men, that showed a 28% reduction in coronary heart disease. Whether the discrepancies are due to gender or dose remains unanswered. While additional trial data would be necessary to fully address this issue, WHS data can be used to determine whether varying usage within the study is a determinant of future CVD events. We propose to use state-of- the art statistical methods to estimate the causal effects of actual aspirin use during the trial to determine if actual use is more predictive of later CVD, and whether higher actual doses used have a greater impact on CVD. In addition, we will use the updated time-varying covariables to examine whether they modify the effect of actual aspirin use during the trial using similar methods. While data for the vitamin E intervention in the WHS are more consistent with previous null trial data, we found a reduction in the secondary endpoint of CVD mortality, as well as effect modification by age. There may be confounding by intermediate events in these data, however, which could distort estimates from both randomized as well as observational analyses. We will thus apply the same causal methods to determine whether there is an effect of actual vitamin E use or dose on the development of CVD after adjusting for time-varying covariables, as well as exploring the presence of modification of the effect of vitamin E. A 2002 recommendation by the Preventive Services Task Force for primary prevention strongly recommended that clinicians consider aspirin chemoprevention for all adults at increased risk of coronary heart disease, including postmenopausal women. The true effect of aspirin in women, and of varying effects by dose, thus has major public health relevance. For vitamin E, data from the WHS support current guidelines stating that use is not justified for CVD reduction. The findings of reduced risk of CVD mortality, however, as well as effects by age, should be explored further to clarify the public health message.