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: 10683741
• 负责人: Lauren Beth Cooper
• 金额: $ 38.78万
• 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/10683741
• 关键词: Acute; Address; Affect; Ancillary Study; Biological; Biological Assay; Biological Markers; Blood; Cardiac; Cessation of life; Clinical; Clinical Trials; Collaborations; Complement; Congestive Heart Failure; 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; blood-based biomarker; clinical efficacy; design; follow-up; improved; insight; mortality; novel; participant enrollment; pragmatic study; prevent; prognostic; prospective; proteomic signature; recruit; sample collection; study population; treatment response; 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.

包括呋塞米和托拉塞米在内的袢利尿剂是治疗心力衰竭最常用的药物之一 （心力衰竭），仍然是这些患者治疗的基础，但仍不确定单袢利尿剂是否有效 应优先使用。托拉塞米和呋塞米可能产生不同影响的方式 心力衰竭患者的结果仍不确定，以及不同人群的效果是否相同 包括性别、种族和射血分数 (EF) 在内的重要亚组尚不清楚。 NIH 资助的务实 TRANFORM-HF 试验正在研究托拉塞米是否与降低死亡率和住院率相关 与呋塞米相比，可以改善生活质量，但不包含机械目标。这 750 名患者 机械辅助研究旨在填补关键知识空白，补充临床发现 TRANSFORM-HF 通过提供机械合理性来潜在地增加研究结果的采用 以支持成果结果。将在基线和 90 天时收集连续血液和尿液样本 然后纵向靶向发现蛋白质组学以及具有已知预后和预后的生物标志物 机制作用将用于阐明潜在差异背后的独特系统生物学 试验中研究的两种袢利尿剂的作用。血液中的纵向蛋白质组测量 尿液将提供同时评估两者的多种相似点和差异的机会 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 克服了先前嵌入临床试验中的机制研究的局限性，这些局限性受到小规模的限制 免疫测定组合，目前包括 100 种或更多蛋白质的精确重复测量，这些蛋白质可以 根据生物学角色进行聚类。我们利用这些混合 ELISA 寡核苷酸的前瞻性试验数据 同时测量 184 种蛋白质的近端延伸测定表明， 使用托拉塞米的患者与使用托拉塞米的患者之间存在介导炎症和纤维化的蛋白质水平 呋塞米。这项基于我们的试点数据的适当动力研究的目的将描述如何 聚集到多种生物学作用的蛋白质和生物标志物的轨迹受到利尿策略的影响 整个辅助研究人群和重要亚组，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，评估以下治疗的效果 利尿策略对肾功能的影响，并确定肾功能下降与尿的关系 肾小管损伤的生物标志物证据。总的来说，从中获得的重点机制见解 辅助研究最终将使临床医生更好地了解袢利尿剂的生理影响 在当代心力衰竭的多种药物治疗中的应用并吸收潜在的临床意义 通过母体临床试验确定利尿剂选择对心脏和肾脏生理学的影响。

项目成果

Proteomic differences among patients with heart failure taking furosemide or torsemide.

心力衰竭患者服用速尿或扭转的患者之间的蛋白质组学差异。

• DOI: 10.1002/clc.23733
• 发表时间: 2022-03
• 期刊: Clinical cardiology
• 影响因子: 2.7
• 作者: Cooper LB;Bruce S;Psotka M;Mentz R;Bell R;Seliger SL;O'Connor C;deFilippi C
• 通讯作者: deFilippi C