The Comparative Effectiveness and Safety of Oral Anticoagulants in Patients with Cirrhosis and Atrial Fibrillation

摘要 肝硬化的患病率和死亡率在过去二十年中急剧增加。心房 纤维性颤动（NVAF）不成比例地影响15%的肝硬化患者，并导致大量的发病率， 死亡率，包括中风率高出5倍。在NVAF的一般人群中， 通常有利于口服抗凝剂（OAC）的启动。相反，超过50%的肝硬化和NVAF患者 由于担心出血，尽管中风风险显著增加，但未进行抗凝治疗， 抗凝质量和福尔斯。这些问题也使最佳OAC方案的选择复杂化， 包括选择华法林和直接口服抗凝剂（DOAC：阿哌沙班、利伐沙班、达比加群 和依度沙班）。虽然DOAC在肝硬化患者中比华法林有潜在的益处，但它们的变化 肝代谢（20%-75%），并且它们在肝硬化中基本上未经测试，因为这些患者 从之前所有针对NVAF的DOAC随机对照试验（RCT）中排除。此外，RCT不太可能 招募并留住患有晚期失代偿性肝硬化或认知障碍的脆弱患者， 常规护理的典型代表。因此，对于肝硬化和NVAF患者， 出血和血栓形成-迫切需要关于最佳OAC策略的可靠数据。 该提案旨在确定华法林和DOAC在以下人群中的相对有效性和安全性- 2011年至2019年期间诊断为肝硬化和NVAF的超过250，000名美国成年人的队列 （包括超过100，000名新的OAC发起人），来自4个医疗保健数据库（Medicare、Medicaid、Truven MarketScan和Optum Clinformatics）。在这个队列中，我们提出：（目标1）定义有效性和 使用与不使用OAC（包括华法林和特定DOAC）的安全性;（目的2）定义比较 启动（2a）华法林与DOAC的有效性和安全性;以及（2b）特定DOAC（即头对头 阿哌沙班与利伐沙班与达比加群与依度沙班的比较）;以及（目的3）确定关键亚组 对OAC特别有益或有害的患者-包括晚期或失代偿期患者 肝硬化、高跌倒风险或预测抗凝质量差。为了最大限度地减少混淆并优化研究 有效性，我们将使用我们的团队开发的创新方法，包括：（i）高维倾向分数; (ii)我们的新的、经验证的用于肝硬化严重程度、跌倒风险和抗凝质量的表型分型算法;以及（iii） 将我们队列的一个子集与来自电子健康记录的丰富临床信息和实验室数据联系起来 (EHR)，用于外部调整和倾向评分校准。完成这些研究将提供 为提供者提供必要的证据基础，以优化脆弱患者的OAC选择和卒中预防 肝硬化和NVAF，产生即时和直接的公共卫生效益。这项工作也将产生 一个易于推广的基础设施，用于稳健地检测慢性肝病患者的药物作用。

ABSTRACT The prevalence of and mortality from cirrhosis have increased dramatically over the past twenty years. Atrial fibrillation (NVAF) disproportionately affects 15% of patients with cirrhosis and leads to substantial morbidity and mortality, including 5-fold higher rates of stroke. In the general population with NVAF, the risk-benefit balance typically favors initiation of oral anticoagulants (OAC). In contrast, over 50% of patients with cirrhosis and NVAF are not anticoagulated despite their markedly increased risk of stroke, due to concerns about bleeding, poor anticoagulation quality and falls. These concerns also complicate selection of an optimal OAC regimen, which involves choosing between warfarin and direct oral anticoagulants (DOAC: apixaban, rivaroxaban, dabigatran and edoxaban). While DOACs have potential benefits over warfarin in patients with cirrhosis, they have variable hepatic metabolism (between 20%-75%) and they are largely untested in cirrhosis, because such patients were excluded from all prior DOAC randomized controlled trials (RCTs) for NVAF. Moreover, RCTs are unlikely to recruit and retain vulnerable patients with advanced, decompensated cirrhosis or cognitive impairments in a manner representative of routine care. Thus, for patients with cirrhosis and NVAF – who are at higher risk of both bleeding and thrombosis – there is a pressing need for robust data regarding the optimal OAC strategy. This proposal seeks to define the comparative effectiveness and safety of warfarin and DOACs in a population- based cohort of over 250,000 U.S. adults with established cirrhosis and NVAF diagnosed between 2011-2019 (including over 100,000 new OAC initiators), from 4 healthcare databases (Medicare, Medicaid, Truven MarketScan and Optum Clinformatics). Within this cohort, we propose: (Aim 1) To define the effectiveness and safety of use vs. non-use of OACs (including warfarin and specific DOACs); (Aim 2) To define the comparative effectiveness and safety of initiating (2a) warfarin vs. DOACs; and (2b) specific DOACs (i.e. head-to-head comparisons of, apixaban vs. rivaroxaban vs. dabigatran vs. edoxaban); and (Aim 3) To identify key subgroups for whom OACs are particularly beneficial or hazardous – including patients with advanced or decompensated cirrhosis, high fall risk or poor predicted anticoagulation quality. To minimize confounding and optimize study validity, we will use innovative methods developed by our team, including: (i) high-dimensional propensity scores; (ii) our novel, validated algorithms for phenotyping cirrhosis severity, fall risk and anticoagulation quality; and (iii) linkage of a subset of our cohort with rich clinical information and laboratory data from electronic health records (EHR), for external adjustment and propensity score calibration. Completing these studies will provide the necessary evidence base for providers to optimize OAC selection and stroke prevention in vulnerable patients with cirrhosis and NVAF, yielding an immediate and direct public health benefit. This work will also produce a readily generalizable infrastructure for robustly detecting drug effects in patients with chronic liver disease.