Outcomes of non-vitamin K anticoagulants in atrial fibrillation

摘要/总结 房颤是最常见的持续性心律失常， 预计到2050年将翻一番，达到800万至1200万。因为超过80%的患者年龄在65岁或 年龄越大，用于这种疾病的医疗保险支出将相应增加，目前总额为8美元。 每年十亿。房颤使中风风险增加五倍，被认为是所有中风的15%; 因此，预防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）-达比加群、利伐沙班、阿哌沙班和依度沙班 - 已取代华法林作为大多数患者的推荐抗凝剂。 多项证据表明NOAC疗效和安全性存在临床重要差异。因素 改变决定抗凝作用的血浆浓度，并且在NOAC之间存在差异 可能影响相对有效性和安全性。尽管NOAC具有相当的半衰期，但利伐沙班和 依度沙班每天服用一次，导致稳态血浆中的变化超过10倍。 对于阿哌沙班和达比加群，每日服用两次，这种变化小于2倍。 质子泵抑制剂降低达比加群的浓度，达比加群需要胃酸来吸收， 并使达比加群显著降低主要上消化道（GI）出血， 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，阿哌沙班的结果优于达比加群或利伐沙班， 强调需要NOAC相对有效性和安全性的可靠数据。然而，现有的/在- 进展性随机对照试验和观察性研究无法提供所需数据。 NOAC消除的并发抑制剂可能会增加大出血的风险。对于一些 对于不常处方的抑制剂，FDA建议NOAC剂量减少。然而，指南不 建议改变最常用的处方抑制剂的做法，增加平均血浆 浓度为1.3至2.2倍，并为至少四分之一的NOAC治疗患者开具处方。 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 和安全性迫切需要为越来越多的房颤患者提供实践信息。 我们将检验以下假设： 目的1：在非瓣膜性房颤患者中，任何卒中/全身性栓塞的发生率（有效性 终点）和出血性中风/致命性出血（安全性终点）在NOAC之间存在差异。 目的2：同时使用NOAC和可能具有临床意义的PGP/CYP 3A 4中效抑制剂 替代品会增加出血性中风/致命性出血的风险。

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.