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

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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.