Dosing of Direct Oral Anticoagulants for stroke prevention in Atrial Fibrillation: Patterns, Consequences, and Guidance

摘要 心房颤动（AF）是一种常见的心律失常，影响美国5%的人口， 65岁，与中风风险增加五倍有关。抗凝剂推荐用于 许多老年房颤患者，以减少中风的风险。自2010年以来，四种新的口服抗凝剂用于 这些药物通常被称为“直接口服”， 抗凝血剂（DOAC），包括达比加群、利伐沙班、阿哌沙班和依度沙班。这些新药 与以前的抗凝治疗方案相比，具有多种优势，导致使用量迅速增加。2014年， 分发了1 000多万份新药处方。 DOAC被认为在大多数患者中具有可预测的抗凝反应。然而有些 患者间药物吸收和消除存在差异，可能导致药物浓度 过高（导致出血风险增加）或过低（导致卒中不充分 预防）。年龄和与年龄相关的慢性疾病，如肾损害，是影响药物治疗的关键因素。 吸收和消除，因此有效性和安全性。对于大多数患者，标准剂量是 适当的（例如，达比加群150 mg每日两次，利伐沙班20 mg每日一次，阿哌沙班5 mg每日两次）。 每种DOAC的较低剂量也被批准用于特定的患者亚群，例如肾功能受损的患者。 函数）。不幸的是，关于低剂量DOAC疗效的信息很少。例如低 达比加群剂量（75 mg）未纳入作为批准基础的RE-LY临床试验 达比加群用于AF相关卒中预防，而低剂量阿哌沙班（2.5 mg）仅用于不到5%的 ARISTOTLE试验中的患者，该试验是批准阿哌沙班的基础。 最近的数据表明，低剂量DOAC的使用正在增加，尽管缺乏证据表明， 服用低剂量DOAC的患者的结局。此外，数据表明DOAC通常不给药 根据制造商指南。适当的DOAC剂量对老年人尤其重要。出血 和中风的风险都随着年龄的增长而增加， 和吸收。特别是，肾脏经历了与年龄相关的变化，这些变化转化为进行性的 随着年龄的增长，肾功能下降。因此，我们的具体目标是： 1.评估新发AF老年患者的DOAC给药，并确定 根据批准的指南，经常抗凝不足或过度。 2.比较抗凝不足、过度或充分的老年患者的结局， 指南结果包括药物使用（例如，依从性、持续性、剂量变化）、临床 结果（例如，死亡、中风、出血）和资源使用（例如，费用）。 3.探索影响低剂量或高剂量DOAC安全性的其他患者特征。

ABSTRACT Atrial fibrillation (AF) is a common disturbance in cardiac rhythm that impacts 5% of the U.S. population over age 65 and is associated with a five-fold increase in the risk of stroke. Anticoagulants are recommended for many elderly patients with AF to reduce the risk of stroke. Since 2010, four new oral anticoagulants for use in non-valvular AF have been approved in the U.S. These drugs are often referred to as ‘direct oral anticoagulants’ (DOAC) and include dabigatran, rivaroxaban, apixaban, and edoxaban. These new drugs have multiple advantages over previous options for anticoagulation, resulting in a rapid increase in use. In 2014, more than 10 million prescriptions for the new drugs were dispensed. DOACs are believed to have a predictable anticoagulation response in most patients. Nevertheless, some variability in drug absorption and elimination across patients exists, possibly resulting in drug concentrations that are either too high (leading to increased bleeding risk), or too low (leading to inadequate stroke prevention). Age and age-related chronic conditions such as renal impairment are key factors that impact drug absorption and elimination, and therefore effectiveness and safety. For most patients, standard doses are appropriate (e.g., dabigatran 150 mg twice daily, rivaroxaban 20 mg once daily, apixaban 5 mg twice daily). Lower doses of each DOAC were also approved for specific patient subsets, such as those with impaired renal function). Unfortunately, information about the efficacy of low dose DOACs is sparse. For example, the low dose dabigatran (75 mg) was not included in the RE-LY clinical trial that was the basis for approving dabigatran for AF-related stroke prevention, while low dose apixaban (2.5 mg) was given to fewer than 5% of patients in the ARISTOTLE trial that was the basis for approving apixaban. Recent data indicates that the use of low dose DOACs is increasing, despite the paucity of evidence regarding outcomes in patients taking low dose DOACs. Moreover, data suggests that DOACs are often not dosed according to manufacturer guidelines. Proper DOAC dosing is particularly important for the elderly. Bleeding and stroke risk both increase with age, as does the presence of other conditions that impact drug elimination and absorption. In particular, the kidney undergoes age-related changes that translate into a progressive decline in renal function as people age. Thus, our specific aims are: 1. Evaluate DOAC dosing in elderly patients with new AF, and identify characteristics of patients who are frequently under- and over- anticoagulated according to approved guidelines. 2. Compare outcomes among elderly patients who are under, over, or adequately anti-coagulated, according to guidelines. Outcomes include medication use (e.g., adherence, persistence, change in dose), clinical outcomes (e.g., death, stroke, bleeding), and resource use (e.g., costs). 3. Explore additional patient characteristics that impact the safety of low or high dose DOACs.