Outcomes of non-vitamin K anticoagulants in atrial fibrillation

摘要/摘要 房颤是最常见的持续性心律失常，其患者数量为 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岁或以上 年龄较大的人，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10亿美元。心房颤动使中风风险增加五倍，被认为是导致15%中风的原因； 因此，预防缺血性中风的抗凝治疗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)--达比加兰、利伐沙班、阿皮沙班和依多沙班 -已取代华法林成为大多数患者推荐的抗凝剂。 有几条证据表明，NOAC的疗效和安全性在临床上存在重要差异。因素 这会改变决定抗凝效果的血浆浓度，并在NOAC之间有所不同 可能会影响相对疗效和安全性。尽管NOAC有类似的半衰期，但利伐沙班和 依多沙班每天服用一次，导致稳态血浆的变化超过10倍 阿皮沙班和达比加兰每天服用两次，这一变化不到2倍。 质子泵抑制剂降低达比加仑的浓度，达比加兰需要胃酸才能吸收， 达比卡特兰显著减少上消化道(GI)大出血。 对于其他NOAC，表明抗凝活性降低。房颤患者的初步数据 在一项胃肠道出血研究中显示，阿皮沙班的疗效好于达比卡特兰或利伐沙班， 强调需要关于NOAC相对有效性和安全性的可靠数据。然而，可用的/在- 进展随机对照试验和观察性研究无法提供所需数据。 同时使用NOAC清除抑制剂可能会增加大出血的风险。对一些人来说 FDA建议减少NOAC的剂量，而不是经常开出的抑制剂。然而，指导方针并不 建议改变最常用的提高平均血浆浓度的处方抑制剂的做法 浓度为1.3至2.2倍，至少四分之一的NOAC治疗患者开出了处方。 这些潜在相互作用的临床效果尚不清楚。 因此，我们将进行一项严格的医疗保险队列研究，以提供NOAC相对疗效的数据 而安全性迫切需要为越来越多的房颤患者的实践提供信息。 我们将检验以下假设： 目的1：在非瓣膜性心房颤动患者中，任何中风/系统性血栓的发生率(疗效 NOAC之间的出血性中风/致命出血(安全终点)和出血性中风/致命出血(安全终点)不同。 目的2：与Pgp/CYP3A4中度抑制剂同时使用具有潜在临床价值的NOAC 替代方案会增加出血性中风/致命出血的风险。

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.