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

口服抗凝药对肝硬化合并心房颤动患者的有效性和安全性比较

基本信息

批准号：
10559071
负责人：
Tracey Simon
金额：
$ 88.91万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-03-01 至 2028-02-29
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10559071
关键词：
Address Adult Adverse event Affect Algorithms Anticoagulants Anticoagulation Ascites Atrial Fibrillation Benefits and Risks Blood Coagulation Disorders Calibration Cause of Death Cirrhosis Clinical Clinical Trials Data Data Set Databases Diabetes Mellitus Diagnosis Dose Effectiveness Electronic Health Record Ensure Epidemic Equilibrium Esophagus Event Exclusion General Population Health Benefit Healthcare Healthcare Systems Hemorrhage Hepatic Hepatic Encephalopathy Impaired cognition Individual Infrastructure Intracranial Hemorrhages Knowledge Laboratories Link Liver Medicaid Medicare Methods Microcirculation Modeling Morbidity - disease rate Obesity Odds Ratio Oral Outcome Patients Peritonitis Pharmaceutical Preparations Pharmacotherapy Phenotype Polypharmacy Portal Hypertension Predictive Value Prevalence Prevention Probability Provider Public Health Randomized, Controlled Trials Regimen Risk Safety Sample Size Severities Stroke Stroke prevention Subgroup Sum Testing Therapeutic Thrombocytopenia Thrombosis Time Uncertainty Vulnerable Populations Warfarin Work aged chronic liver disease clinical care cohort comparative effectiveness comparative safety cost drug metabolism drug testing effectiveness outcome electronic health data end stage liver disease evidence base fall risk falls flexibility frailty head-to-head comparison high dimensionality high risk high risk population improved innovation liver metabolism mortality novel patient population phenotyping algorithm population based predictive tools recruit routine care safety outcomes selective prevention stroke risk

项目摘要

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.

抽象的过去二十年来，肝硬化的患病率和死亡率急剧增加。纤维性颤动 (NVAF) 不成比例地影响 15% 的肝硬化患者，并导致严重的发病率和死亡率，包括 NVAF 普通人群中卒中发生率高出 5 倍，风险与收益平衡。相比之下，超过 50% 的肝硬化和 NVAF 患者通常倾向于开始口服抗凝剂 (OAC)。尽管由于担心出血，中风风险显着增加，但并未抗凝这些问题也使最佳 OAC 方案的选择变得复杂。涉及在华法林和直接口服抗凝剂（DOAC：阿哌沙班、利伐沙班、达比加群）之间进行选择虽然 DOAC 对肝硬化患者具有优于华法林的潜在益处，但它们的疗效存在差异。肝脏代谢（20%-75% 之间），并且在很大程度上未经肝硬化测试，因为此类患者被排除在所有先前的 DOAC NVAF 随机对照试验 (RCT) 之外，而且，RCT 不太可能被排除。招募并留住患有晚期、失代偿性肝硬化或认知障碍的弱势患者因此，对于患有肝硬化和 NVAF 的患者来说，他们的风险较高。出血和血栓形成——迫切需要有关最佳 OAC 策略的可靠数据。该提案旨在确定华法林和 DOAC 在人群中的相对有效性和安全性： 2011 年至 2019 年间诊断出的超过 250,000 名患有肝硬化和 NVAF 的美国成年人的队列（包括超过 100,000 个新的 OAC 发起者），来自 4 个医疗保健数据库（Medicare、Medicaid、Truven MarketScan 和 Optum Clinformatics）。在这个队列中，我们建议：（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（目标 2）定义比较起始 (2a) 华法林与 DOAC 的有效性和安全性；和 (2b) 特定 DOAC（即）阿哌沙班、利伐沙班、达比加群、依度沙班的比较）；以及（目标 3）确定关键亚组 OAC 对哪些人特别有益或特别危险——包括晚期或失代偿的患者肝硬化、高跌倒风险或预测的抗凝质量较差，以尽量减少混杂因素并优化研究。为了验证有效性，我们将使用我们团队开发的创新方法，包括：（i）高维度倾向得分； (ii) 我们针对肝硬化严重程度、跌倒风险和抗凝质量进行表型分析的新颖且经过验证的算法；以及 (iii) 将我们队列的一部分与电子健康记录中丰富的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。提供者优化 OAC 选择和弱势患者中风预防的必要证据基础肝硬化和 NVAF，这项工作也将产生直接的公共卫生效益。一个易于推广的基础设施，用于可靠地检测慢性肝病患者的药物作用。