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.

项目总结 直接作用口服抗凝剂(DOAC)现在是预防中风的首选抗凝剂。 非瓣膜性心房颤动(NVAF)患者正在取代华法林静脉治疗 血栓栓塞性疾病。NVAF是一种常见的老年人慢性病，发病率最高的是 年龄超过80岁，但高龄成年人在很大程度上被排除在DOAC疗效试验之外。这一赤字是 非常年长的NVAF患者与参加临床试验的较年轻的NVAF患者不同，因为他们经常 有其他慢性疾病接受多种药物治疗，女性比例高于男性， 可能降低了肾脏和肝脏的药物清除，并增加了跌倒和出血的风险。我们假设 非常老的NVAF患者的DOAC浓度将比临床试验中看到的更高。我们有 初步数据显示，低于建议剂量的剂量达到的浓度与 推荐剂量和推荐剂量产生的浓度远远超过 一种DOAC(阿匹沙班)的临床试验。我们建议测量利伐沙班(仅限肾脏清除量)和 APIXABAN(细胞色素P3A4/5代谢和肾脏清除)因子Xa在缓解期NVAF患者中的浓度 75岁，按提供者规定的剂量接受这些DOAC的临床适应症治疗。我们会比较一下 将浓度数据添加到临床疗效试验报告中，并探索患者级别的特征(例如 年龄、性别、种族、肥胖、肾功能、临床情况、联合用药、虚弱)，以确定相关因素 低谷和峰值浓度位于临床试验预期范围之外。如果我们的工作证实 老年NVAF患者的DOAC浓度高于预期，这两者都有 对未来研究和当前临床护理的影响。这项工作将确立对更大最终版本的需求 评估老年患者不同剂量策略的临床结果的研究，并提供了对 在临床人群中估计样本大小的潜在差异和变异性 更大的权威性研究。该数据还可以识别潜在的责任机制的贡献者 临床亚组差异，以此作为进一步假设检验的基础。结果也可能立即 对患有NVAF的老年患者的临床护理的影响不同于随机试验中的患者 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 在已公布的指导方针之外。