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

基本信息

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
项目类别：
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

项目摘要

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心房颤动（NVAF）的患者正在取代华法林以治疗静脉血栓栓塞疾病。 NVAF是在患病率最高的老年人中常见的慢性病。 80岁以上的年龄，但非常老的成年人在很大程度上被排除在DOAC的功效试验之外。这种赤字是关键，因为NVAF的非常古老的患者与参加临床试验的年轻NVAF患者不同，因为他们经常还有其他用多种药物治疗的慢性疾病，女性比例更高，男性比例更高可能减少了肾脏和肝药物清除率，增加了跌倒和出血的风险。我们假设那个非常古老的NVAF患者的DOAC浓度将比临床试验中所见。我们有初步数据显示，低于建议的给药浓度类似建议的给药和建议的给药产生的浓度远远超过了一个DOAC（Apixaban）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患者的apixaban（CYP3A4/5代谢和肾脏清除）Xa浓度 75岁的人以其提供者的规定剂量接受这些DOAC进行临床适应症。我们将比较集中数据到临床疗效试验的报告并探讨患者水平特征（例如年龄，性别，种族，肥胖，肾功能，临床状况，共同药物，脆弱），以识别相关因素临床试验的范围内的谷槽和峰值浓度范围。如果我们的工作确认 NVAF的老年患者达到了高于预期的DOAC浓度，这两者都具有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评估老年患者不同给药策略的临床结果的研究，并提供估计值临床人群中差异和可变性的潜在幅度估计这些样本量更大的确定性研究。数据还可以确定负责基本机制的潜在贡献者对于临床亚组差异，以基于进一步的假设检验。结果也可能立即对老年NVAF患者的临床护理与随机试验中的临床护理不同。在临床护理期间或考虑给药时，用于监测因子XA抑制或DOAC浓度除已发布的准则外。