Interactions of Enzyme-Inducing Antiepileptic Drugs with Direct-Acting Oral Anticoagulants: Risk of Thromboembolic Events

项目摘要/摘要 全球有超过7000万人患有癫痫，其中美国估计有340万人。多个广泛的- 使用的抗癫痫药物(AEDs)具有非靶向作用，诱导关键的药物代谢酶，产生 大量潜在的药物-药物相互作用(DDiS)。一个这样的互动与特别高的现实世界 据称，这些酶诱导的抗癫痫药物之间存在相关性，但临床证据很少。 (EI-AEDs)和直接作用口服抗凝剂(DOAC)。AEDs与抗凝剂的联合处方是 常见是由于癫痫和DOAC的主要适应症之间的频繁并发和因果联系。 EI-AEDs诱导DOAC吸收和代谢的两个关键成分，这可能导致较低的， 潜在的亚治疗，DOAC水平，以及血栓栓子事件的风险增加。证据： 这些DDIS主要由体外和动物数据组成。现有的人体研究局限于现实世界 由于两者的适用性：研究结果的实质性不一致，以及将研究置于高风险中的方法 因为偏见和混淆。此外，这些人类研究狭隘地关注成对的EI-AED/DOAC相互作用 忽视更高级别的药物-药物-药物相互作用(3DI)的潜在作用，特别是考虑到 多种药物在癫痫人群中的流行率。这项研究计划的目标是在方法论上应用 严谨的设计和利用大规模的行政索赔数据，以解决有关真实- 世界DOAC治疗失败与EI-AED和伴随的药物相互作用有关。在目标1中，我们将 采用回溯性事件使用者队列设计比较成年癫痫患者的血栓栓塞率 暴露于含有EI-AEDs的DOAC与暴露于含非酶的DOAC的活性对照组的比较 诱导抗癫痫药(NEI-AEDs)。鉴于利用率和血栓风险的关键差异，我们将分别分析 DOAC用于房颤(1A)和深静脉血栓/肺血栓(1B)。产生效果 对观测和未观测的混杂因素进行有力控制的估计(通过代理调整)，数据自适应 将采用高维倾向评分。在目标2中，我们将使用病例交叉设计来探索 3DIs在成年癫痫患者服用EI-AEDs和DOAC的血栓栓塞症事件中的作用。其中的一部小说- 将根据伴随药物的时间关联进行3DI筛查的人员方法 血栓栓塞症。估计数将与NEI规定的阴性病例组进行定量比较- AEDs与DOAC一起使用，以减轻伴随药物的直接影响和混杂，以及 区分3DI和DDI信号。总体而言，这项研究将有助于推动处方的发展 为需要抗凝的癫痫患者提供标准，并为未来的3DI研究提供基准。 从导师指导的研究和培训中获得的宝贵技能和经验将是必不可少的 为申请者建立持续的博士后研究计划和迈向职业生涯的基础 作为一名独立的研究员兼临床医生，专门从事神经流行病学和药物流行病学。

Project Summary/Abstract Epilepsy affects over 70 million people worldwide, including an estimated 3.4 million in the US. Multiple widely- used antiepileptic drugs (AEDs) have off-target effects inducing key drug metabolizing enzymes, yielding numerous potential drug-drug interactions (DDIs). One such interaction with particularly high real-world relevance, but minimal clinical evidence, has been purported to occur between these enzyme-inducing AEDs (EI-AEDs) and direct-acting oral anticoagulants (DOACs). Co-prescription of AEDs with anticoagulants is common due to the frequent concurrency and causal links between epilepsy and the main indications for DOACs. EI-AEDs induce two crucial components of DOAC absorption and metabolism, which may lead to lower, potentially sub-therapeutic, levels of DOACs, and an increased risk of thromboembolic events. Evidence for these DDIs is composed primarily of in vitro and animal data. Existing human studies have limited real-world applicability due to both: substantial inconsistencies in findings, and methods that put the research at high risk for bias and confounding. Further, these human studies’ narrow focus on pairwise EI-AED/DOAC interactions disregards the potential role of higher-order drug-drug-drug interactions (3DIs), particularly given the high prevalence of polypharmacy in epilepsy populations. The goal of this research plan is to apply methodologically rigorous designs and leverage large-scale administrative claims data to address knowledge gaps regarding real- world DOAC therapeutic failures associated with EI-AED and concomitant drug interactions. In Aim 1, we will use a retrospective incident user cohort design to compare thromboembolic event rates in adults with epilepsy exposed to DOACs with EI-AEDs versus an active comparator group exposed to DOACs with non-enzyme inducing AEDs (NEI-AEDs). Given critical differences in utilization and thrombotic risk, we will separately analyze DOAC use for atrial fibrillation (1A) and deep vein thrombus/pulmonary embolism (1B). To generate effect estimates with vigorous control for observed and unobserved confounders (via proxy-adjustment), data-adaptive high-dimensional propensity scoring will be employed. In Aim 2, we will use a case-crossover design to explore the role of 3DIs in thromboembolic events in adults with epilepsy prescribed EI-AEDs and DOACs. A novel within- person approach to 3DI screening will be undertaken based on the temporal associations of concomitant drugs with thromboembolic events. Estimates will be quantitatively compared to a negative case group prescribed NEI- AEDs with DOACs in order to mitigate the direct effects and confounding by concomitant drugs, as well as to differentiate 3DI from DDI signals. Overall, this research will contribute to the advancement of prescribing standards for epilepsy patients requiring anticoagulation and provide benchmarks for future 3DI investigations. The valuable skills and experiences gained from this mentor-guided research and training will serve as essential foundations for the applicant to build continued postdoctoral research initiatives, and to advance towards a career as an independent investigator-clinician specializing in neuroepidemiology and pharmacoepidemiology.