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

基本信息

批准号：
10578795
负责人：
WAYNE A RAY
金额：
$ 81.55万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-01 至 2025-02-28
项目状态：
未结题

项目摘要

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/摘要心房颤动的患者人数，最常见的持续性心律不齐，是预计到2050年，预计将翻倍至8-1200万。由于超过80％的患者年龄在65岁或年龄较大，这种疾病的医疗保险支出将相应增加，现在总计8美元每年十亿美元。心房颤动增加了中风的风险五倍，被认为会导致所有中风的15％。因此，防止缺血性中风的抗凝是治疗的主要组成部分。近年来非维生素K拮抗剂口服抗凝剂（NOAC） - Dabigatran，Rivaroxaban，Apixaban和Edoxaban - 已代替华法林，是大多数患者推荐的抗凝剂。几条证据表明，NOAC效率和安全性在临床上的重要差异。因素这种改变了血浆浓度，该血浆浓度决定了抗凝作用，而NOAC之间的不同可能影响相对效率和安全性。尽管NOAC具有可比的半衰期，Rivaroxaban和每天服用Edoxaban，导致稳态等离子体的10倍以上浓度，而对于apixaban和dabigatran，每天服用两次，这种变化小于2倍。质子 - 泵抑制剂降低了dabigatran的浓度，这需要胃酸才能滥用滥用，会议大大减少了大型胃肠道（GI）出血，而达比加特兰的降低比对于其他NOAC，表明抗凝活性降低。房颤患者的初步数据在GI出血研究中，与Dabigatran或Rivaroxaban相比，Apixaban的结果更好强调对NOAC相对效率和安全性可靠数据的需求。但是，可用/in- 进步RCT和观察性研究无法提供所需的数据。 NOAC消除的并发抑制剂可能会增加大出血的风险。对于某些人 FDA不经常处方抑制剂，建议降低NOAC剂量。但是，指南没有建议对最常见的规定抑制剂的建议更改的实践，这些抑制剂增加了平均等离子体浓度为1.3至2.2倍，并针对NOAC治疗的至少四分之一的患者处方。这些潜在相互作用的临床效果尚不清楚。这是我们将进行严格的Medicare队列研究，以提供有关NOAC相对效率的数据迫切需要安全的安全性来为越来越多的心房颤动患者提供练习。我们将测试以下假设： AIM 1：在非浮力心房颤动的患者中，任何中风/全身性栓塞的事件（功效 NOAC之间的终点）和出血性中风/致命的出血（安全终点）不同。目标2：同时使用具有潜在临床的PGP/CYP3A4中等抑制剂的NOACS 替代方案增加了出血性中风/致命出血的风险。