Predictors of hemorrhage among patients on direct acting oral anticoagulants

摘要： 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，在房颤（AF）患者中取代华法林， 静脉血栓栓塞（VTE）。然而，出血（HEM）是最可怕的不良反应， 这些有效疗法的关键障碍。抗凝血剂一直排在首位 在美国，药物不良事件相关住院的违法者中，HEM约占80%， ADM是S离子。 为了预测HEM的风险，研究人员已经制定了主要针对华法林的临床预测规则（CPR）- 有关HEM然而，缺乏DOAC相关HEM的CPR，抗血小板药物的可变纳入， 缺乏对胃保护治疗或相互作用药物（影响APX和RIVA）的评估 药代动力学），缺乏对整个肾功能谱的风险评估，以及缺乏（以 无）黑人的代表性是关键的知识差距。查明造成儿童死亡率上升的因素 APX和RIVA使用者的HEM风险以及阐明其影响（效应量）至关重要 在本申请中，我们的目标是确定HEM风险的预测因子，并定义临床研究中的影响（效应量）。 接受APX（n=1500）和RIVA（N=1500）治疗并发生CPR的医学复杂、种族多样的患者队列 APX相关的HEM和RIVA相关的HEM。 通过目标1，我们将确定和评估预测因素（例如人口统计学、合并症）对 HEM的风险在目标2中，我们将阐明抗血小板治疗、胃保护性治疗和抗血小板治疗的联合使用对 治疗（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使用者中HEM风险的影响。目标3将侧重于确定 慢性肾病（CKD）谱对HEM风险的影响，并阐明稳态药代动力学（PK）， 在RIVA和APX使用者之间的整个肾功能谱的药效学（PD）。目标4 将把目标1-3的结果纳入CPR的构建中，以个性化APX中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观察到的复杂患者，并对未充分研究的患者进行了稳健的代表性 （黑人，中度和重度CKD患者）和常见合并用药评估改善 对真实的世界患者的普遍性和适用性。

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.