Predictors of hemorrhage among patients on direct acting oral anticoagulants

直接作用口服抗凝剂患者出血的预测因素

基本信息

批准号：
10549820
负责人：
NITA A LIMDI
金额：
$ 72.99万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-05-20 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10549820
关键词：
Accounting Admission activity Adverse drug event Adverse effects American Heart Association Amiodarone Anticoagulant therapy Anticoagulants Anticoagulation Atrial Fibrillation Benefits and Risks Black Populations Blood Platelets Characteristics Chronic Chronic Kidney Failure Clinical Complex Dialysis procedure Diltiazem Dose Drug Interactions Drug Kinetics Elderly Equation Exposure to Fright Genotype Glomerular Filtration Rate Guidelines H2 gene Health Benefit Hemorrhage Hospitalization Impairment Individual Institution International Ions Kidney Knowledge Marketing Medical Monitor Oral Patient Recruitments Patients Pharmaceutical Preparations Pharmacodynamics Pharmacogenomics Phenotype Predictive Factor Prevalence Prevention Proton Pump Inhibitors Public Health Recommendation Renal function Research Research Personnel Risk Risk Assessment Risk Reduction Seminal Verapamil Warfarin clinical practice clinical predictors cohort comorbidity demographics efficacious treatment genetic predictors high risk improved improved outcome individual patient men offender older patient personalized medicine personalized predictions pharmacokinetics and pharmacodynamics population health predictive modeling prospective racial disparity racial diversity recruit response risk prediction stroke risk trend venous thromboembolism

项目摘要

ABSTRACT: Direct acting oral anticoagulants (DOAC), specifically rivaroxaban (RIVA) and apixaban (APX) have emerged as the most commonly used oral anticoagulants, replacing warfarin in patients with atrial fibrillation (AF) and venous thromboembolism (VTE). However, hemorrhage (HEM) is the most feared adverse effect and is a critical barrier to institution of these efficacious therapies. Anticoagulants have consistently ranked as the top offenders for adverse drug event related hospitalizations in the US, with HEM accounting for ~80% of adm is s ions . To predict HEM risk, investigators have developed clinical prediction rules (CPRs) focused mainly on warfarin- related HEM. However, the lack of CPRs for DOAC-related HEM, the variable inclusion of antiplatelets, the lack of assessment of gastro-protective therapies or interacting drugs (influencing APX and RIVA pharmacokinetics), the lack of assessment of risk across the spectrum of kidney function, and the scarce (to nil) representation of Blacks are critical knowledge gaps. Identifying factors contributing to the increased HEM risk among APX and RIVA users and elucidating their impact (effect size) is of critical importance In this application, we aim to identify predictors of HEM risk and define the impact (effect size) in a clinical cohort of medically complex, racially diverse patients on APX (n=1500) and RIVA (N=1500) and develop CPRs for APX-related-HEM and RIVA-related-HEM. Through Aim 1, we will identify and assess the influence of predictors (e.g. demographics, comorbidities) on risk of HEM. In Aim 2, we will elucidate the influence concomitant use of antiplatelet therapy, gastro-protective therapies (proton pump inhibitors and H2 Receptor Blockers) and interacting drugs (amiodarone, diltiazem and verapamil) on risk of HEM among RIVA and APX users. Aim 3 will focus on determining the influence of chronic kidney disease (CKD) spectrum on HEM risk and elucidate steady state pharmacokinetics (PK) and pharmacodynamics (PD) across the spectrum of kidney function among RIVA and APX users. Finally, Aim 4 will incorporate results from Aims 1-3 into building CPRs to personalize the prediction of HEM among APX and RIVA users. The prediction models will validated in an independent cohort (n=500 APX, n=500 RIVA). Our focus on complex patients seen in clinical practice with robust representation of understudied patients (Blacks, patients with moderate and severe-CKD) and assessment of common co-medications improves generalizability and applicability to real world patients.

抽象的：直接作用口服抗凝剂（DOAC），特别是利伐沙班（RIVA）和阿哌沙班（APX）已经出现作为最常用的口服抗凝剂，在心房颤动 (AF) 患者中取代华法林静脉血栓栓塞（VTE）。然而，出血 (HEM) 是最令人担心的不良反应，也是一种常见的不良反应。建立这些有效疗法的关键障碍。抗凝剂一直稳居榜首在美国，因药物不良事件相关住院的罪犯中，HEM 约占 80% adm 是 s 离子。为了预测 HEM 风险，研究人员制定了主要针对华法林的临床预测规则 (CPR) 相关的HEM。然而，缺乏针对 DOAC 相关 HEM 的心肺复苏、抗血小板药物的可变性、缺乏对胃保护疗法或相互作用药物（影响 APX 和 RIVA）的评估药代动力学）、缺乏对整个肾功能范围的风险评估以及稀缺（ nil) 黑人的代表性是关键的知识差距。确定导致增加的因素 APX 和 RIVA 用户中的 HEM 风险以及阐明其影响（效应大小）至关重要在此应用中，我们的目标是确定 HEM 风险的预测因素并定义临床中的影响（效应大小）由医学复杂、种族多样的患者组成的队列，使用 APX (n=1500) 和 RIVA (N=1500) 并制定心肺复苏 (CPR) 适用于 APX 相关的 HEM 和 RIVA 相关的 HEM。通过目标 1，我们将识别并评估预测因素（例如人口统计、合并症）对 HEM 的风险。在目标 2 中，我们将阐明同时使用抗血小板治疗、胃保护药物的影响疗法（质子泵抑制剂和 H2 受体阻滞剂）和相互作用药物（胺碘酮、地尔硫卓和维拉帕米）对 RIVA 和 APX 用户中 HEM 风险的影响。目标 3 将侧重于确定以下因素的影响：慢性肾脏病 (CKD) 谱对 HEM 风险的影响并阐明稳态药代动力学 (PK) 和 RIVA 和 APX 用户肾功能范围内的药效学 (PD)。最后，目标4 将把目标 1-3 的结果纳入构建 CPR 中，以个性化 APX 和 HEM 的预测 RIVA 用户。预测模型将在独立队列（n=500 APX，n=500 RIVA）中进行验证。我们专注于临床实践中看到的复杂患者，并具有充分代表性的未充分研究的患者（黑人、中度和重度 CKD 患者）和常见联合用药的评估得到改善对现实世界患者的普遍性和适用性。

项目成果

期刊论文数量（66）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Rare variant association testing by adaptive combination of P-values.

通过 P 值的自适应组合进行罕见变异关联测试。

DOI：
发表时间：
2014
期刊：
影响因子：
3.7
作者：
Lin, Wan;Lou, Xiang;Gao, Guimin;Liu, Nianjun
通讯作者：
Liu, Nianjun

Genetic variants associated with warfarin dose in African-American individuals: a genome-wide association study.

与非洲裔美国人华法林剂量相关的遗传变异：一项全基因组关联研究。

DOI：
发表时间：
2013-08-31
期刊：
影响因子：
0
作者：
Perera, Minoli A;Cavallari, Larisa H;Limdi, Nita A;Gamazon, Eric R;Konkashbaev, Anuar;Daneshjou, Roxana;Pluzhnikov, Anna;Crawford, Dana C;Wang, Jelai;Liu, Nianjun;Tatonetti, Nicholas;Bourgeois, Stephane;Takahashi, Harumi;Bradford, Yukiko;Bur
通讯作者：
Bur

Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Pharmacogenetics-Guided Warfarin Dosing: 2017 Update.

临床药物遗传学实施联盟 (CPIC) 药物遗传学指导华法林剂量指南：2017 年更新。

DOI：
发表时间：
2017-09
期刊：
影响因子：
6.7
作者：
Johnson, J A;Caudle, K E;Gong, L;Whirl;Stein, C M;Scott, S A;Lee, M T;Gage, B F;Kimmel, S E;Perera, M A;Anderson, J L;Pirmohamed, M;Klein, T E;Limdi, N A;Cavallari, L H;Wadelius, M
通讯作者：
Wadelius, M

Pharmacogenetics in Cardiovascular Medicine.

心血管医学中的药物遗传学。