The optimal loop diuretic: mechanistic insights from longitudinal changes in blood and urine proteins to explain efficacy and safety of torsemide vs furosemide after a heart failure hospitalization

最佳袢利尿剂：从血液和尿蛋白的纵向变化中获得机制见解，以解释心力衰竭住院后托拉塞米与呋塞米的疗效和安全性

• 批准号: 10462616
• 负责人: Lauren Beth Cooper
• 金额: $ 38.81万
• 依托单位: INOVA HEALTH CARE SERVICES
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10462616
• 关键词: Acute; Address; Affect; Ancillary Study; Biological; Biological Assay; Biological Markers; Blood; Cardiac; Cessation of life; Clinical; Clinical Trials; Collaborations; Complement; Data; Diuretics; Drug usage; EFRAC; Enrollment; Enzyme-Linked Immunosorbent Assay; Fibrosis; Foundations; Functional disorder; Funding; Furosemide; Gender; Heart failure; Hospitalization; Hospitals; Hybrids; Immunoassay; Inflammation; Injury; Kidney; Kidney Diseases; Knowledge; Left Ventricular Ejection Fraction; Measurement; Measures; Mediating; Oligonucleotides; Outcome; Parents; Pathway interactions; Patient-Focused Outcomes; Patients; Persons; Physiological; Physiology; Pilot Projects; Proteins; Proteomics; Quality of life; Race; Randomized; Recording of previous events; Recovery; Renal function; Role; Safety; Series; Specimen; Study Subject; Subgroup; Systems Biology; Technology; Time; Tubular formation; United States National Institutes of Health; Urine; base; blood-based biomarker; clinical efficacy; design; follow-up; improved; insight; mortality; novel; prevent; prognostic; prospective; protein biomarkers; proteomic signature; recruit; sample collection; study population; treatment response; trial comparing; uptake; urinary

Loop diuretics including furosemide and torsemide are among the most commonly used drugs for heart failure (HF) and remain the foundation of therapy for these patients, but it remains uncertain if one loop diuretic should be used preferentially. The manner by which torsemide and furosemide may differentially affect outcomes for patients with HF remains undetermined, and whether the effects are homogenous across important subgroups including gender, race, and ejection fraction (EF) is unknown. The NIH-funded pragmatic TRANFORM-HF trial is studying whether torsemide is associated with reduced mortality and hospitalizations and improved quality of life compared to furosemide, but contains no mechanistic aims. This 750-patient mechanistic ancillary study is designed to fill a critical knowledge gap, complementing the clinical findings of TRANSFORM-HF by potentially augmenting uptake of the study findings by providing mechanistic plausibility to support the outcome results. Serial blood and urine specimens will be to collected at baseline and 90-days and then longitudinal targeted discovery proteomics along with biomarkers with known prognostic and mechanistic roles will be used to elucidate the unique systems biology underlying the potential differential effects of the two loop diuretics studied in the trial. Longitudinal proteomic measurements within blood and urine will provide the opportunity to simultaneously asses multiple similarities and differences of the two diuretics on cardiac, renal and systemic pathophysiology. Recent advances in proteomic technology have overcome prior limitations of mechanistic studies embedded within clinical trials that were limited by a small portfolio of immunoassays, by now including precise repeated measures of 100 or more proteins which can be clustered according to biological roles. Our prospective pilot data utilizing these hybrid ELISA-oligonucleotide proximal extension assays to simultaneously measure 184 proteins suggests that many differences in inflammation and fibrosis mediating protein levels are present between patients using torsemide vs furosemide. The aims of this appropriately powered study based on our pilot data will describe how the trajectory of proteins and biomarkers clustered to multiple biologic roles are influenced by diuretic strategy in the entire ancillary study population and important subgroups including gender, race, and baseline EF. This study will also determine the trajectory of renal function decline post HF hospitalization, estimate the effect of diuretic strategy on renal function and determine the association of renal function decline with urinary biomarker evidence of tubular injury. In aggregate, the focused mechanistic insights obtained from this ancillary study will ultimately allow clinicians to better understand the physiologic implications of loop diuretic use in the contemporary polydrug management of HF and assimilate the potential clinical implications identified by the parent clinical trial of diuretic choice on cardiac and renal physiology.

包括速尿和速尿在内的环状利尿剂是治疗心力衰竭最常用的药物。 (HF)，并仍然是这些患者治疗的基础，但仍不确定是否为一循环利尿剂 应优先使用。速尿和速尿可能产生不同影响的方式 心衰患者的结局尚不确定，以及这些影响是否在所有患者中都是一致的 包括性别、种族和射血分数(EF)在内的重要亚组尚不清楚。美国国立卫生研究院资助的务实项目 Transform-HF试验正在研究托塞米特是否与降低死亡率和住院率有关 与速尿相比，生活质量得到了改善，但没有机械性的目的。这位750名患者 机械性辅助研究旨在填补关键的知识空白，补充临床研究结果 通过提供机制上的似是而非，潜在地增加对研究结果的吸收，从而转化-HF 以支持结果结果。连续的血液和尿液样本将在基线和90天内采集 然后纵向靶向发现蛋白质组学以及具有已知预后和 机械论角色将被用来阐明潜在差异背后的独特系统生物学 试验中研究的两种环状利尿剂的效果。血液和血液中的纵向蛋白质组学测量 尿液将提供机会，同时评估两者的多个相似和不同之处 利尿剂对心脏、肾脏和全身病理生理学的影响。蛋白质组学技术的最新进展 克服了嵌入临床试验中的机械性研究的先前限制，这些研究受到小范围限制 免疫分析组合，现在包括对100或更多蛋白质的精确重复测量，这些蛋白质可以 根据生物角色进行分类。我们利用这些杂交的酶联免疫吸附试验-寡核苷酸的预期试验数据 同时测量184个蛋白质的近端延伸分析表明，在 服用托塞米特的患者与服用托塞米特的患者之间存在炎症和纤维化中介蛋白水平 速尿。这项基于我们的试点数据的适当支持的研究的目的将描述 利尿剂策略对聚集在多种生物学作用上的蛋白质和生物标志物的影响 整个辅助研究人群和重要的亚组，包括性别、种族和基线EF。这 研究还将确定心力衰竭住院后肾功能下降的轨迹，估计 利尿策略对肾功能的影响及肾功能下降与尿量的关系 肾小管损伤的生物标志物证据。总体而言，从这一过程中获得的专注于机械论的见解 辅助研究最终将使临床医生更好地了解环状利尿剂的生理意义 在当代心力衰竭多药治疗中的应用及其潜在的临床意义 经家长临床试验确定利尿剂的选择对心脏和肾脏的生理影响。