Supplement to Direct-Acting Oral Anticoagulants: Anticoagulant Activity in Understudied Older NVAF Patients

项目摘要 直接作用口服抗凝剂（DOAC）现在是预防中风的首选抗凝剂， 非瓣膜性房颤（NVAF）患者，正在替代华法林治疗静脉 血栓栓塞性疾病NVAF是老年人中常见的慢性疾病， 年龄超过80岁，但非常老的成年人在很大程度上被排除在DOAC的疗效试验之外。这一赤字是 关键是，年龄很大的NVAF患者与参加临床试验的年轻NVAF患者不同，因为他们通常 有其他慢性病，用多种药物治疗，女性比例高于男性， 可能降低肾脏和肝脏的药物清除率，增加福尔斯和出血的风险。我们假设 高龄NVAF患者的DOAC浓度将高于临床试验中所见。我们有 初步数据显示，低于推荐剂量达到的浓度与 推荐剂量和推荐剂量产生的浓度远远超过在 一种DOAC（阿哌沙班）的临床试验。我们建议测量利伐沙班（仅肾清除率）， 稳定NVAF患者中阿哌沙班（CYP 3A 4/5代谢和肾清除率）因子Xa浓度超过 年龄75岁，接受这些DOAC的临床适应症，剂量由他们的供应商规定。我们将比较 将浓度数据与临床疗效试验的报告进行比较，并探索患者水平特征（如 年龄、性别、种族、肥胖、肾功能、临床状况、合并用药、虚弱），以确定相关因素 谷浓度和峰浓度超出临床试验的预期范围。如果我们的工作证实 老年NVAF患者的DOAC浓度高于预期， 对未来研究和当前临床护理的影响。这项工作将建立更大的确定性的需要， 评估老年患者不同给药策略的临床结局的研究，并提供了 临床人群的潜在差异和变异性程度，以估计这些人群的样本量 更大的确定性研究。这些数据还可以识别潜在的贡献者， 临床亚组差异作为进一步假设检验的基础。结果也可能立即 影响老年NVAF患者的临床护理，与随机试验不同， 用于在临床护理期间或考虑给药时监测因子Xa抑制或DOAC浓度 在已发布的指南之外。

PROJECT SUMMARY Direct acting oral anticoagulants (DOACs) are now the anticoagulants of choice for prevention of stroke in patients with non-valvular atrial fibrillation (NVAF) and are replacing warfarin for treatment of venous thromboembolic disease. NVAF is a common chronic condition in older adults with the highest prevalence at ages over 80 years, yet very old adults have been largely excluded from efficacy trials of DOACs. This deficit is key as very old patients with NVAF differ from younger NVAF patients enrolled in clinical trials as they often have other chronic conditions treated with multiple medications, have a higher proportion of women than men, may have reduced renal and hepatic drug clearance, and increased risk of falls and bleeding. We hypothesize that very old NVAF patients will have higher DOAC concentrations than seen in the clinical trials. We have preliminary data showing that lower than recommended dosing achieved concentrations similar to recommended dosing and recommended dosing produced concentrations far in excess of those seen in the clinical trials for one DOAC (apixaban). We propose to measure rivaroxaban (renal clearance only) and apixaban (CYP3A4/5 metabolism and renal clearance) factor Xa concentrations in stable NVAF patients over age 75 receiving these DOACs for clinical indications at doses prescribed by their providers. We will compare the concentration data to reports from clinical efficacy trials and explore patient level characteristics (such as age, sex, race, obesity, renal function, clinical conditions, co-medications, frailty), to identify factors associated with trough and peak concentrations that lie outside ranges expected from clinical trials. If our work confirms that higher than expected DOAC concentrations are reached in older patients with NVAF, it has both implications for future research and current clinical care. The work will establish the need for larger definitive studies assessing clinical outcomes of varying dosing strategies in older patients, and, provide estimates of potential magnitudes of difference and variability in clinical populations to estimate sample sizes for these larger definitive studies. The data may also identify potential contributors to underlying mechanism responsible for clinical subgroup difference on which to base further hypothesis testing. The results may also immediately impact clinical care of older patients with NVAF that differ from those in randomized trials by suggesting a role for monitoring factor Xa inhibition or DOAC concentrations during clinical care or when considering dosing outside of published guidelines.