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: 10074852
• 负责人: Lauren Beth Cooper
• 金额: $ 41.88万
• 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/10074852
• 关键词: Acute; Address; Affect; Ancillary Study; Asses; 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.

循环利尿剂在内，包括速尿和扭矩是心力衰竭最常用的药物之一 （HF）并仍然是这些患者治疗的基础，但仍不确定一个循环是利尿剂 应该优先使用。扭转和速尿可能差异影响的方式 HF患者的结局仍未确定，以及这些影响是否均匀 包括性别，种族和射血分数（EF）在内的重要亚组是未知的。 NIH资助的务实 Tranform-HF试验正在研究torsemide是否与死亡率降低和住院相关 与速尿相比，生活质量的改善，但没有任何机械目的。这个750患者 机械辅助研究旨在填补关键的知识差距，以补充 通过提供机械合理性来扩大研究结果的吸收来转换HF 支持结果结果。连环血和尿液标本将在基线和90天收集 然后纵向有针对性的发现蛋白质组学以及具有已知预后和的生物标志物 机械作用将用于阐明潜在差异的唯一系统生物学 在试验中研究了两个循环利尿剂的影响。血液中的纵向蛋白质组学测量 尿液将提供同时估算两者中多个相似性和差异的机会 关于心脏，肾脏和系统病理生理学的利尿剂。蛋白质组学技术的最新进展已 克服嵌入在临床试验中的机理研究的先前局限 免疫测定的投资组合，到现在包括100个或更多蛋白质的精确重复测量 根据生物学角色聚集。我们利用这些混合ELISA-寡核苷酸的潜在试点数据 同时测量184种蛋白质的近端扩展测定表明， 患者之间存在炎症和纤维化介导蛋白水平的蛋白质水平 速尿。根据我们的飞行员数据，这项适当动力研究的目的将描述 聚集在多种生物学作用的蛋白质和生物标志物的轨迹受利尿剂策略的影响 整个辅助研究人群以及包括性别，种族和基线EF在内的重要亚组。这 研究还将确定HF住院后肾功能下降的轨迹，估计 利尿策略在肾功能方面并确定肾功能下降与尿的关联 生物标志物肾小管损伤的证据。总体而言，从此获得的集中机械见解 辅助研究最终将使临床医生能够更好地了解循环利尿剂的生理意义 用于HF的当代聚力管理并吸收潜在的临床意义 通过在心脏和肾脏生理学上的利尿剂选择的父临床试验确定。