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

直接作用口服抗凝剂的补充：正在研究的老年 NVAF 患者的抗凝活性

• 批准号: 10297780
• 负责人: MARGARET C. FANG
• 金额: $ 9.69万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-15 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10297780
• 关键词: Academic Medical Centers; Adult; Age; Aged, 80 and over; American; Anticoagulants; Anticoagulation; Atrial Fibrillation; Biological Assay; CYP3A4 gene; Characteristics; Chronic; Clinic; Clinical; Clinical Trials; Creatinine; Creatinine clearance measurement; Data; Disease; Dose; Drug Interactions; Elderly; Enrollment; Factor Xa; Food; Guidelines; Hemorrhage; Hepatic; High Prevalence; Institution; Investigation; Kidney; Low Prevalence; Measures; Metabolism; Monitor; Obesity; Oral; Outcome; Outpatients; Patients; Pharmaceutical Preparations; Population; Prevention; Provider; Publishing; Race; Recommendation; Renal clearance function; Renal function; Reporting; Role; Safety; Sample Size; Sampling; Stroke; Stroke prevention; Subgroup; Testing; Venous; Warfarin; Weight; Woman; Work; absorption; base; clinical care; clinical encounter; dosage; drug clearance; drug metabolism; efficacy clinical trial; efficacy trial; experience; fall risk; frailty; men; novel therapeutics; older patient; randomized trial; response; sex; venous thromboembolism

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.

项目概要 直接作用口服抗凝剂（DOAC）现在是预防卒中的首选抗凝剂 患有非瓣膜性心房颤动 (NVAF) 并正在替代华法林治疗静脉曲张的患者 血栓栓塞性疾病。 NVAF 是老年人中常见的慢性病，​​发病率最高的是 年龄超过 80 岁，但高龄成年人基本上被排除在 DOAC 的功效试验之外。这个赤字是 关键是，高龄 NVAF 患者与参加临床试验的年轻 NVAF 患者不同，因为他们经常 患有其他需要多种药物治疗的慢性疾病，女性比例高于男性， 可能会降低肾脏和肝脏的药物清除率，并增加跌倒和出血的风险。我们假设 高龄 NVAF 患者的 DOAC 浓度将高于临床试验中的水平。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了所见的浓度 一种 DOAC（阿哌沙班）的临床试验。我们建议测量利伐沙班（仅肾脏清除率）和 稳定 NVAF 患者中阿哌沙班（CYP3A4/5 代谢和肾清除率）因子 Xa 浓度超过 75 岁，根据其提供者规定的剂量接受这些 DOAC 用于临床适应症。我们会比较 临床疗效试验报告中的浓度数据并探索患者水平特征（例如 年龄、性别、种族、肥胖、肾功能、临床状况、联合用药、虚弱），以确定相关因素 谷浓度和峰值浓度超出了临床试验的预期范围。如果我们的工作证实 患有 NVAF 的老年患者达到的 DOAC 浓度高于预期， 对未来研究和当前临床护理的影响。这项工作将确定需要更大的确定性 研究评估老年患者不同剂量策略的临床结果，并提供估计 临床人群中差异和变异的潜在程度，以估计这些样本的样本量 更大规模的确定性研究。该数据还可以识别潜在的贡献者负责的底层机制 用于进一步假设检验的临床亚组差异。结果也可能立即 对 NVAF 老年患者临床护理的影响与随机试验中的不同，表明了一种作用 用于在临床护理期间或考虑给药时监测 Xa 因子抑制或 DOAC 浓度 超出已发布的指南。