Outcomes of non-vitamin K anticoagulants in atrial fibrillation

非维生素 K 抗凝剂治疗心房颤动的结果

• 批准号: 10360648
• 负责人: WAYNE A RAY
• 金额: $ 82.04万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10360648
• 关键词: ABCB1 gene; Acidity; Affect; Age-Years; Amiodarone; Anticoagulants; Anticoagulation; Arrhythmia; Atrial Fibrillation; Brain hemorrhage; CYP3A4 gene; Clarithromycin; Clinical; Coagulation Process; Code; Cohort Studies; Cytochrome P450; Data; Diagnosis; Diltiazem; Disease; Dose; Drug Interactions; Electronic Health Record; Embolism; Enzymes; Erythromycin; Event; Expenditure; Gastrointestinal Hemorrhage; Guidelines; Hemorrhage; Hepatic; Hour; Incidence; Individual; Ischemic Stroke; Label; Link; Medicare; Observational Study; Oral; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Plasma; Proton Pump Inhibitors; Regimen; Risk; Safety; Stomach; Stroke; Testing; Thromboembolism; Variant; Verapamil; Warfarin; absorption; antagonist; clinical effect; clinical practice; cohort; gastrointestinal; high risk; inhibitor; mortality; multi drug transporter; prevent; stroke risk; thrombotic

ABSTRACT/SUMMARY The number of patients with atrial fibrillation, the most common sustained cardiac arrhythmia, is projected to double to 8-12 million by 2050. Because more than 80% of patients are 65 years of age or older, there will be a corresponding increase in Medicare expenditures for this disease, which now total $8 billion annually. Atrial fibrillation increases stroke risk five-fold and is thought to cause 15% of all strokes; thus, anticoagulation to prevent ischemic strokes is a primary component of treatment. In recent years the non-vitamin K antagonist oral anticoagulants (NOACs)—dabigatran, rivaroxaban, apixaban, and edoxaban —have replaced warfarin as the recommended anticoagulant for most patients. Several lines of evidence indicate clinically important differences in NOAC efficacy and safety. Factors that alter plasma concentrations, which determine the anticoagulant effect, and differ between the NOACs could affect relative efficacy and safety. Although the NOACs have comparable half-lives, rivaroxaban and edoxaban are taken once daily, resulting in more than a 10-fold variation in steady-state plasma concentrations, whereas for apixaban and dabigatran, taken twice daily, this variation is less than 2-fold. Proton-pump inhibitors reduce concentrations of dabigatran, which requires gastric acidity for absorption, and confer a substantially greater reduction in major upper gastrointestinal (GI) bleeds for dabigatran than for other NOACs, suggesting reduced anticoagulant activity. Preliminary data from atrial fibrillation patients in a GI bleeding study indicate better outcomes for apixaban than for dabigatran or rivaroxaban, underscoring the need for reliable data on NOAC relative efficacy and safety. However, the available/in- progress RCTs and observational studies cannot provide the needed data. Concurrent inhibitors of NOAC elimination potentially increase the risk of major bleeding. For some infrequently prescribed inhibitors, the FDA recommends NOAC dose reduction. However, guidelines do not recommend changed practice for the most commonly prescribed inhibitors which increase mean plasma concentrations 1.3 to 2.2-fold and are prescribed for at least one-fourth of patients with NOAC treatment. The clinical effects of these potential interactions are unknown. Thus, we will conduct a rigorous Medicare cohort study to provide the data on NOAC relative efficacy and safety urgently needed to inform practice for the growing number of patients with atrial fibrillation. We will test the hypotheses that: Aim 1: In patients with non-valvular atrial fibrillation, the incidence of any stroke/systemic embolus (efficacy endpoint) and hemorrhagic stroke/fatal bleed (safety endpoint) differs between the NOACs. Aim 2: Concurrent use of NOACs with moderate inhibitors of PGP/CYP3A4 that have potential clinical alternatives increases the risk of hemorrhagic stroke/fatal bleed.

摘要/总结 患有房颤（最常见的持续性心律失常）的患者数量为 预计到 2050 年，这一数字将翻一番，达到 8-1200 万。因为超过 80% 的患者年龄在 65 岁或 年纪大了，针对这种疾病的医疗保险支出也会相应增加，目前总计8美元 每年 10 亿美元。心房颤动使中风风险增加五倍，并被认为是导致所有中风的 15%； 因此，抗凝预防缺血性中风是近年来治疗的主要组成部分。 非维生素 K 拮抗剂口服抗凝剂 (NOAC)——达比加群、利伐沙班、阿哌沙班和艾多沙班 —已取代华法林成为大多数患者的推荐抗凝剂。 多项证据表明 NOAC 功效和安全性因素在临床上存在重要差异。 改变血浆浓度，从而决定抗凝作用，并且 NOAC 之间存在差异 尽管 NOAC 具有相似的半衰期，但利伐沙班和 艾多沙班每天服用一次，导致稳态血浆变化超过 10 倍 浓度，而对于阿哌沙班和达比加群，每天服用两次，这种变化小于两倍。 质子泵抑制剂降低达比加群的浓度，达比加群需要胃酸才能吸收， 与达比加群相比，达比加群显着减少主要上消化道 (GI) 出血 对于其他 NOAC，表明来自心房颤动患者的抗凝活性降低。 胃肠道出血研究表明阿哌沙班的疗效优于达比加群或利伐沙班， 强调需要有关 NOAC 疗效相对性和安全性的可靠数据。 进展随机对照试验和观察性研究无法提供所需的数据。 对于某些人来说，同时使用 NOAC 消除抑制剂可能会增加大出血的风险。 对于不常用的抑制剂，FDA 建议减少 NOAC 剂量，但指南中并未建议。 建议改变最常用的抑制剂的做法，这些抑制剂会增加平均血浆 浓度为 1.3 至 2.2 倍，并用于至少四分之一接受 NOAC 治疗的患者。 这些潜在相互作用的临床影响尚不清楚。 因此，我们将进行严格的医疗保险队列研究，以提供 NOAC 相对疗效的数据 迫切需要安全性来为越来越多的房颤患者提供实践指导。 我们将检验以下假设： 目标 1：在非瓣膜性心房颤动患者中，任何卒中/全身性栓塞的发生率（疗效 NOAC 之间的终点）和出血性中风/致命性出血（安全终点）有所不同。 目标 2：同时使用 NOAC 与具有临床潜力的 PGP/CYP3A4 中度抑制剂 替代品会增加出血性中风/致命失血的风险。