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.

包括速尿和托塞米在内的循环利尿剂是治疗心力衰竭最常用的药物

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