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

袢利尿剂包括呋塞米和托拉塞米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，但仍不确定是否有一种袢利尿剂 应该优先使用。托拉塞米和呋塞米可能不同地影响 HF患者的结局仍不确定， 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，提高了生活质量，但不含机械目的。750患者 机械辅助研究旨在填补关键的知识空白，补充临床发现， 通过提供机械可接受性，潜在增加研究结果的吸收，从而转化HF 以支持结果。将在基线和90天时采集系列血液和尿液样本 然后纵向靶向发现蛋白质组学沿着与生物标志物， 机械作用将被用来阐明潜在差异的独特系统生物学 试验中研究的两种袢利尿剂的效果。血液中的纵向蛋白质组学测量， 尿液将提供同时评估两者的多种相似性和差异的机会， 利尿剂对心脏、肾脏和全身病理生理的影响。蛋白质组学技术的最新进展 克服了先前在临床试验中嵌入的机制研究的局限性，这些局限性受到小的 免疫测定组合，到目前为止，包括100种或更多蛋白质的精确重复测量， 根据生物学作用分类。我们的前瞻性试验数据利用这些杂交ELISA-寡核苷酸 同时测量184种蛋白质的近端延伸测定表明， 在使用托拉塞米的患者与 呋塞米。基于我们的试点数据，这项具有适当把握度的研究的目的将描述 蛋白质和生物标志物的轨迹聚集到多个生物学作用的影响，利尿策略， 整个辅助研究人群和重要亚组，包括性别、人种和基线EF。这 研究还将确定HF住院后肾功能下降的轨迹，估计 利尿策略对肾功能的影响，并确定肾功能下降与尿 肾小管损伤的生物标志物证据。总的来说，从这一点中获得的集中的机械论见解 一项辅助研究将最终使临床医生更好地了解袢利尿剂的生理意义 用于当代HF的多种药物管理，并吸收潜在的临床意义 通过利尿剂选择对心脏和肾脏生理学的母临床试验确定。

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.