AIMS:Congestion signals heart failure progression and drives decompensation. Reliable management strategies remain poorly developed. We evaluated 12-months of congestion-guided clinical management following implantation of an inferior vena cava (IVC) sensor. METHODS AND RESULTS:Data were combined from two prospective studies (FUTURE-HF and FUTURE-HFII) (N=65, mean age 65.7±9.5 years; 75.4% NYHA III; 90.8% HFrEF). Patients recorded daily IVC parameters. Adjudicated safety outcomes, sensor-derived IVC area measurement versus CT imaging, medication adjustments, and clinical outcomes at 12-months were analysed.No adjudicated device or procedure-related serious adverse events occurred. Excellent correlation was observed between sensor-derived and CT-derived IVC area (n=44; R2=0.97; mean relative error <5%). Patient adherence was 93% and a sustained, significant reduction in IVC area was observed (8.1%, p<0.005), correlated with clinical improvements (p<0.001), despite no significant change in body weight. Improvements were observed in NYHA functional class (Class III: 74.5% improved to 40.0%; p<0.01) and NT-proBNP (median 1697 reduced to 998 ng/L; p<0.001). HF events (HFEs) were lower post-implant (0.31/year, 1.67/year pre-implant; 84.5% relative reduction; rate ratio: 0.18; 95% CI: 0.08-0.29). Medication adjustments (n=415) included diuretic titration (57%) and increased use of guideline directed medical therapy from baseline to 12-months (28%). CONCLUSIONS:Congestion management through ambulatory IVC monitoring demonstrated excellent safety, sustained accuracy, and high levels of patient adherence at 12-months after sensor implantation. This was associated with improved HF congestion status and a lower observed rate of HFEs, supporting investigation of congestion-guided management using IVC monitoring in a pivotal randomized clinical trial.

BACKGROUND:Prior self-management strategies to prevent heart failure (HF) hospitalizations using symptoms and weight have shown limited effectiveness caused by delayed and nonspecific signals. Ambulatory congestion monitoring may enable safe and actionable self-management. OBJECTIVES:The purpose of this study was to evaluate the safety, feasibility of signal-driven intervention, and clinical signals associated with physician-directed patient self-management using an implantable inferior vena cava (IVC) sensor. METHODS:The authors performed a comparison of 2 sequential prospective cohorts enrolled in FUTURE-HFII (Early Feasibility Study of the NORM System in Heart Failure Patients) using an IVC-based congestion management system: clinician-managed care (n = 15) and physician-directed patient self-management (n = 10). The sole difference between cohorts was the smartphone delivery of prespecified physician-developed care plans to patients. Outcomes included safety, device adherence, medication adjustments, congestion metrics, HF events, and quality of life at 90 days. RESULTS:Across 1,927 measurements, daily usage was high in both groups and numerically greater with self-management (90.5% vs 84.8%). No safety signals were observed, and congestion control (NORM score time-in-range) was comparable between groups. Signal intervention frequency was higher with self-management (10.4 vs 2.8 diuretic changes per patient; RR: 3.71; P < 0.01). HF events were directionally lower in the self-managed cohort (0.11 vs 0.33 events/patient-month; RR: 0.30 [95% CI: 0.04-2.57]). Quality-of-life scores improved in both groups, with larger gains (≥5 points in Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score) in the self-managed cohort (60.0% vs 46.7%). CONCLUSIONS:Physician-directed patient self-management using ambulatory IVC-based congestion monitoring was feasible, associated with increased signal-driven intervention, and not associated with adverse safety signals. This strategy demonstrated favorable clinical signals. These findings support further evaluation of congestion-based self-management strategies in a randomized trial. (Early Feasibility Study of the NORM System in Heart Failure Patients [FUTURE-HFII]; NCT05763407).

AIMS:For many years, fluid and sodium restriction have been considered an essential strategy for achieving effective decongestion in acute heart failure (AHF), but this paradigm has recently been questioned. This analysis aims to evaluate and compare the effectiveness of three different fluid strategies for decongestion: no fluid, fluid with sodium/chloride, and fluid without sodium/chloride in AHF. METHODS:This post-hoc analysis of two prospective, single-centre, mechanistic studies included 55 patients with AHF and fluid overload. All patients received standardized furosemide dosing. A total of 21 patients received a continuous infusion of 0.9% NaCl (83 mL/h), 19 patients received 5% glucose (83 mL/h), and 15 did not receive any fluids. The primary outcome is urine volume and natriuresis at 6 h after loop diuretic administration. RESULTS:There was a significant difference in cumulative (6 h) net natriuresis between patients receiving fluid therapy (n = 40) and those without fluid therapy (n = 15) (139 [66-264] mmol vs. 79 [15-144] mmol, P = .043). There was no significant difference in cumulative net diuresis between these groups (1170 [880-1890] mL vs. 1010 [475-1270] mL, P = .078), respectively. The NaCl group had a better diuretic response when compared with the glucose and no-fluids groups (absolute: 1980 [1620-3150] mL vs. 1510 [1075-2175] mL vs. 1010 [475-1270] mL, P < .001, net: 1480 [1120-2650] mL vs. 1010 [575-1675] mL vs. 1010 [475-1270] mL, P = .019, respectively) but the difference in natriuresis did not meet statistical significance (P = .126). CONCLUSION:Intravenous fluid replacement during decongestion in patients with AHF was associated with increased net natriuresis and a trend towards higher urine output, with a significant augmentation of diuresis with sodium chloride supplementation.

BACKGROUND AND HYPOTHESIS:The association between acute declines in estimated glomerular filtration rate (eGFR) among individuals admitted for acute decompensated heart failure (ADHF) and cardiovascular outcomes has been inconsistent. Our objective was to examine whether eGFR decline, and the timing of these declines, are associated with mortality and a composite outcome of mortality or heart failure (HF) hospitalization. METHODS:We used data from the CLOROTIC Trial, which randomized patients admitted for ADHF to thiazide versus placebo. We examined %eGFR change at 2-days (n = 225) and at 4-days (n = 218) after randomization. Multivariable Cox models were used to evaluate the association between % eGFR change and a primary outcome of mortality and secondary outcome of composite of mortality or HF hospitalization. RESULTS:Median %eGFR change was -9.7% (IQR -22.1, 5.4) and -14.4% (-25.1, 7.8) in the thiazide arm at 2-days and 4-days respectively, compared to -0.3% (-7.5, 10.1) and 0% (-10.0, 16.2) in the placebo arm at 2-days and 4-days, respectively. Over a median 3-month follow-up, of those with 2-day eGFR change available, 41 (18%) patients died and 98 (44%) met the composite outcome, and of those with 4-day eGFR change available, 38 (17.4%) died and 95 (43.6%) met the composite outcome. The eGFR decline at 2-days was not associated with risk of mortality (HR = 0.96 [95% CI 0.47, 1.97] and HR = 0.89 [0.37, 2.10] per 30% eGFR decline in the thiazide and placebo arms, respectively). The eGFR decline at 4-days was not associated with risk of mortality in the thiazide arm (HR = 0.86 [0.48, 1.55] per 30% eGFR decline) nor in the placebo (HR = 1.63 [0.82, 3.26] per 30% eGFR decline). Associations were similar for the composite outcome. CONCLUSIONS:Among patients admitted for ADHF and randomized to thiazide vs placebo, early acute declines in eGFR had no association with increased risk of cardiovascular outcomes. REGISTRATION:Clinicaltrials.gov: NCT01647932; EudraCT Number: 2013-001852-36.

Managing cardiorenal syndrome in acute decompensated heart failure remains a major challenge in contemporary cardiology. While pharmacological decongestion with diuretics is the cornerstone of therapy and is effective in most patients, worsening renal function and diuretic resistance continue to pose challenges in selected cases. Device-based therapies are increasingly explored to target key pathophysiological mechanisms underlying cardiorenal dysfunction. This expert review builds on a conceptual framework for device-based therapies. Rather than cataloguing individual technologies, we apply a functional framework that classifies devices according to their primary mode of action: reduction of venous or lymphatic congestion ('pullers'), augmentation of arterial perfusion ('pushers'), and direct removal of sodium and/or fluid ('removers'). For each category, we integrate pathophysiological rationale with available clinical evidence, highlighting the predominance of early-phase physiological evidence and the need for randomized studies demonstrating benefit beyond optimized contemporary medical care.

Background and Aims:Pragmatic clinical trials are designed to assess interventions in real-world settings, and their broad inclusion criteria and clinical variability create valuable opportunities for exploring heterogeneity of treatment effects. In this context, TRANSFORM-HF was a pragmatic trial that found no overall survival difference between torsemide and furosemide in patients hospitalized with heart failure (HF), highlighting the importance of analytic strategies that can uncover clinically meaningful variation in treatment response.The aim of this study was to evaluate whether baseline patient characteristics modify the relative survival benefit of torsemide versus furosemide using machine learning methods. Methods:This was a post hoc analysis of the pragmatic, multicenter, open-label, randomized TRANSFORM-HF trial, which enrolled 2,859 patients hospitalized with HF across 60 US hospitals and randomized them to torsemide or furosemide. More than 50 baseline covariates were incorporated into a Bayesian Accelerated Failure Time model with Bayesian Additive Regression Trees (AFT-BART) to estimate individualized survival treatment effects (ISTEs). The outcome of interest was all-cause mortality over follow-up. Machine learning analyses estimated ISTEs for each patient and identified key baseline covariates modifying relative treatment effects. An exploratory decision tree was used to aid interpretability and to highlight influential effect modifiers. Results:While the overall trial showed no survival difference, machine learning analyses revealed heterogeneity in treatment effects. Atrial fibrillation (AF), BNP/NT-proBNP levels, and prior loop diuretic use emerged as the most influential baseline modifiers. Patients without AF, with lower BNP levels, and without prior loop use showed suggestive benefit from torsemide (fitted mean ISTE up to 0.49; 95% CrI, -0.07 to 1.04), whereas patients with AF, elevated BNP and prior loop use showed relative benefit with furosemide (fitted mean ISTE -0.40; 95% CrI, -0.78 to -0.05). Although most subgroup effect estimates were statistically inconclusive due to wide credible intervals, split points were statistically significant, highlighting the importance of candidate modifiers. Conclusions:In this exploratory AI-driven analysis of TRANSFORM-HF, we identified meaningful heterogeneity in diuretic response, with atrial fibrillation, natriuretic peptide levels, and prior diuretic use modifying relative survival benefit. These findings illustrate how integrating artificial intelligence into the analysis of pragmatic trials can move beyond average treatment effects to generate individualized, hypothesis-generating insights, and underscore the value of anticipating and systematically evaluating treatment-effect heterogeneity when designing and interpreting pragmatic cardiovascular trials. What is the clinical question being addressed?:To apply artificial intelligence to detect treatment effect heterogeneity in the pragmatic TRANSFORM HF trial and to identify patient subgroups with differential benefit from torsemide versus furosemide, supporting precision medicine in heart failure. What is the main finding?:Machine learning analyses within this pragmatic trial revealed substantial heterogeneity in the survival effects of torsemide versus furosemide. Torsemide appeared more beneficial among patients without atrial fibrillation and with lower BNP/NT-proBNP levels, whereas furosemide was favored in those with atrial fibrillation, higher BNP/NT-proBNP concentrations, and prior loop diuretic use. Exploratory analyses demonstrated that applying AI-driven methods to evaluate treatment effect heterogeneity within a pragmatic trial framework can leverage the inherent clinical diversity of pragmatic designs and potentially generate personalized and practice-relevant insights from pragmatic clinical research.

RATIONALE & OBJECTIVE:Inconsistencies in the association of acute declines in kidney function with longer-term cardiovascular (CV) and kidney outcomes in patients with acute heart failure (AHF) may be due to different approaches to assessing the timing of the decline. This study examined the influence of the timing of acute kidney function decline among patients with AHF on the associations of these declines with mortality, CV outcomes, and long-term kidney function. STUDY DESIGN:Observational analysis of clinical trial data. SETTING & PARTICIPANTS:Participants in the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study With Tolvaptan (EVEREST) trial hospitalized for AHF. EXPOSURE:Kidney function decline (defined by creatinine increase by ≥0.3 mg/dL, creatinine increase by >50%, and percentage of creatinine change) at 3 different time points (3, 7, and 14 days after randomization). OUTCOME:Mortality, a composite of CV mortality or heart failure (HF) hospitalization, incident estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2, and a >40% eGFR decline. ANALYTICAL APPROACH:Analytical Approach: Multivariable cause-specific proportional hazards regression models. RESULTS:Among 3,931 patients over a median follow-up of 9.9 months, acute kidney function decline at 3 days was not associated with mortality (HR, 0.98 [95% CI, 0.88-1.09] per 30% creatinine increase) or with the composite outcome of CV mortality and HF hospitalization (HR, 0.96 [95% CI, 0.89-1.05]). By contrast, acute kidney function decline at 7 days after randomization was associated with a higher risk of mortality (HR, 1.19 [95% CI, 1.10-1.30] per 30% creatinine increase) and the composite outcome (HR, 1.10 [95% CI, 1.03-1.18]). Acute kidney function decline at 14 days after randomization also was associated with a higher risk of mortality (HR, 1.27 [95% CI, 1.16-1.38] per 30% creatinine increase) and the composite outcome (HR, 1.15 [95% CI, 1.08-1.23]). Acute kidney function declines at 3, 7, and 14 days after randomization were all associated with significantly higher risk of incident eGFR < 30 mL/min/1.73 m2 and >40% eGFR decline. LIMITATIONS:Limited generalizability from the study of clinical trial participants. CONCLUSIONS:Among patients hospitalized for AHF, incorporating the timing of acute kidney function declines may inform prognostic assessment of CV end points. Acute declines in kidney function at all studied time points were associated with worse longer term kidney function. PLAIN-LANGUAGE SUMMARY:Acute declines in kidney function are frequently encountered among patients admitted for acute heart failure. Using data from the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study With Tolvaptan (EVEREST) trial, we evaluated whether the timing of an acute decline in kidney function may inform the relationship of those declines with the risk of death and other adverse cardiovascular outcomes. We found that early declines in kidney function 3 days after randomization were not associated with death or cardiovascular outcomes. However, declines occurring at 14 days and as early as 7 days were associated with higher risks. Declines at any of these times were associated with worse kidney function over time.

BACKGROUND AND AIMS:Low-dose mineralocorticoid receptor antagonists (MRAs) are guideline-recommended heart failure (HF) therapies. However, MRAs increase aldosterone production, and the sub-saturating doses utilized may allow continued mineralocorticoid receptor (MR) stimulation. The aim of the current analysis was to understand how baseline and change in aldosterone concentrations during MRA therapy impacts MR activity and clinical outcomes. METHODS:HF cohorts with MRA exposure and plasma aldosterone concentrations available were included in patient-level, pooled cohort analyses [DOSE, CARRESS-HF, MDR, and TOPCAT (n = 1019)]. In the MDR cohort (n = 136), urine sodium to potassium ratio was utilized to quantitate MR activity. The relationship of pre-MRA aldosterone concentration, MRA use, and clinical outcomes were meta-analysed utilizing the above pooled cohorts in addition to the EARLIER (n = 300) and EPHESUS (n = 453) trials. RESULTS:MRA use was associated with significantly higher median aldosterone concentrations [MRA = 310 (interquartile range, IQR 180, 533) pg/mL vs no MRA = 174 (IQR 106, 299) pg/mL, P < .001] in the pooled cohort. In the MDR cohort, higher aldosterone was correlated with higher MR activity, with a similar relationship on MRA (r = -.52, P < .001) vs off MRA (r = -.44, P < .001, P interaction = .65), differing only in that higher aldosterone concentrations were required on MRA to achieve the same level of MR activity. In patients with high pre-MRA aldosterone, new MRA initiation reduced MR activity, but MRA initiation increased MR activity in patients with low pre-MRA aldosterone [median change in urine Na/K with high aldosterone =1.4 (IQR 1.1, 2.9) vs low aldosterone = -.9 (IQR -2.1, -.1), P < .001]. In the pooled cohort, the association between MRA use and clinical outcomes was dependent on pre-MRA aldosterone concentration (P interaction = .005). In patients with high pre-MRA aldosterone, MRA was associated with substantially improved clinical outcomes [hazard ratio (HR) .63, 95% confidence interval (CI) .42-.92, P = .02]. However, in patients with low pre-MRA aldosterone, MRA use was associated with worse clinical outcomes (HR 1.66, 95% CI 1.12-2.45, P = .01). CONCLUSIONS:Low-dose MRAs significantly increase aldosterone but inadequately block MR activity (measured by urine Na/K) at these new higher aldosterone concentrations. In patients with high pre-MRA aldosterone, MRA use is associated with improved MR activity and clinical outcomes. However, in patients with lower pre-MRA aldosterone concentrations, MRA use is associated with worsened MR activity and clinical outcomes. MRAs remain guideline-directed HF medications with established population level benefit, but these hypothesis-generating findings indicate additional research is warranted to understand if outcomes can be further improved.

AIMS:Early identification of poor diuretic response is central to acute heart failure (AHF) care, yet the recommended post-diuretic urine sodium (uNa+) thresholds are neither prospectively derived nor validated. We aimed to derive and validate clinically actionable urinary biomarker thresholds to identify poor diuretic response. METHODS AND RESULTS:In this prospective derivation-validation study, 336 AHF patients formed the derivation cohort, and 141 patients formed the validation cohort. Spot urinary biomarkers were measured 2h after loop diuretic administration. Diuretic resistance was defined as urine output <500 mL/6 h, and insufficient diuretic response as <1000 mL/6 h. In the derivation cohort, optimal uNa thresholds were <60 mmol/L and <90 mmol/L, respectively. For diuretic resistance, uNa+ <60 mmol/L showed 0.80 (95%CI: 0.65 -0.90) sensitivity, 0.94 (95%CI: 0.90-0.96) specificity, and an area under the curve (AUC) of 0.93 (95%CI: 0.90-0.97). For insufficient diuretic response, uNa+ <90 mmol/L showed 0.80 (95%CI: 0.69-0.86) sensitivity, 0.84 (95%CI: 0.787-0.878) specificity, and an AUC of 0.86 (95%CI: 0.83-0.93). In the validation cohort, uNa+ <60 mmol/L had numerically higher sensitivity than uNa+ <50 mmol/L (0.87 (95%CI: 062 -0.98) vs. 0.73 (95%CI: 0.48- 0.89)), with similar specificity (0.94 (95%CI: 0.89 -0.97) vs. 0.97 (95%CI: 0.92-0.99)) for diuretic resistance. For insufficient diuretic response, uNa+ <90 mmol/L had higher sensitivity: 0.86 (95%CI: 0.71-0.94) than lower thresholds, with specificity: 0.83 (95%CI: 0.75 -0.89). CONCLUSIONS:In AHF, data-derived post-diuretic uNa+ thresholds of <60 mmol/L and <90 mmol/L identify diuretic resistance and insufficient diuretic response, respectively. Further research and broad external validation are needed.

BACKGROUND:Acoramidis achieves near-complete (≥90%) transthyretin stabilization and is approved to reduce cardiovascular-related mortality and hospitalization in transthyretin amyloid cardiomyopathy. Its effects on kidney function are not well characterized. METHODS:Data from randomized phase 2 (N=49) and phase 3 (N=632) studies in transthyretin amyloid cardiomyopathy were included. The estimated glomerular filtration rate (eGFR) slope was generated using a linear spline mixed-effects model. The urinary albumin-to-creatinine ratio was measured longitudinally. Relationships between changes in kidney function and clinical outcomes were explored using Cox proportional hazards models. RESULTS:Acoramidis initiation resulted in a modest acute dip in eGFR that was dose-dependent, reversible, and not associated with adverse kidney-related events. At Day 28, the mean (±SE) dip in eGFR from baseline with acoramidis was 8.5±0.48 mL/min per 1.73 m2; the placebo-corrected reduction in the urinary albumin-to-creatinine ratio was 15.5% (95% CI, 0.4%-28.4%; P=0.044). The rate of decline in kidney function (chronic eGFR slope) was significantly improved with acoramidis versus placebo (-1.01 versus -3.48 mL/min per 1.73 m2 per year; P<0.001), and the reduction in the urinary albumin-to-creatinine ratio was sustained (13.7% [95% CI, 1.7%-24.2%]; P=0.026) over time. Concomitant tafamidis use did not influence the chronic eGFR slope in either arm. Comparing acoramidis versus placebo subgroups with acute eGFR dips ≥ the median (4.89 mL/min per 1.73 m2) favored acoramidis for all-cause mortality or cardiovascular-related hospitalization (hazard ratio, 0.42 [95% CI, 0.22-0.78]; P=0.006; P interaction=0.043) and cardiovascular-related hospitalization (hazard ratio, 0.34 [95% CI, 0.17-0.66]; P=0.002, P interaction=0.025). Within the placebo arm, eGFR dips portended worse outcomes. CONCLUSIONS:Acoramidis initiation resulted in an acute dip in eGFR and reductions in both the chronic eGFR slope and urinary albumin-to-creatinine ratio versus placebo without adverse kidney-related events. Acoramidis effects on kidney function may be mediated through direct kidney-protective hemodynamic effects. Importantly, the acute dip in eGFR was associated with a reduced risk of adverse clinical outcomes within the first year. REGISTRATION:URL: https://www.clinicaltrials.gov; Unique identifiers: NCT03458130, NCT03536767, NCT03860935, NCT04988386.

Background The Reprieve System is designed to overcome barriers limiting safe and rapid decongestion with individualized automated diuretic titration, real-time diuretic response monitoring, and individualized sodium chloride replacement to prevent cardio-renal dysfunction. Objectives This study aims to establish proof-of-concept that the Reprieve System can facilitate rapid and safe decongestion. Methods FASTR (Fluid Management of Acute Decompensated Heart Failure Subjects Treated With Reprieve Decongestion Management System [DMS]) was a randomized pilot trial comparing the Reprieve System vs a control strategy of optimal diuretic therapy (ODT) in hospitalized patients with acute heart failure. The primary efficacy endpoint was 24-hour natriuresis, and the primary safety endpoint was a composite of dialysis or doubling of creatinine levels, severe electrolyte abnormalities, hypotension, or hypertensive emergency. Results A total of 100 patients were enrolled, with 96 receiving randomized treatment (Reprieve, n = 52; ODT, n = 44). At baseline, the median estimated glomerular filtration rate was 49 mL/min/1.73 m2 (Q1-Q3: 36-78 mL/min/1.73 m2) with estimated excess fluid volume of 20 lbs (Q1-Q3: 15-35 lbs). Twenty-four-hour natriuresis was significantly greater with the Reprieve System (1,082 ± 487 mmol) vs ODT (423 ± 290 mmol; P < 0.001). The safety endpoint occurred in 31% of the Reprieve group vs 39% of the ODT group (P = 0.42). Intravenous diuretic therapy duration was shorter with Reprieve [46 hours [Q1-Q3: 29-80 hours]) vs ODT (88 hours [Q1-Q3: 44-143 hours]; P = 0.014). The rate of weight loss (P = 0.002), net fluid loss (P = 0.03), and net natriuresis (P < 0.001) were significantly faster with Reprieve. Change in serum creatinine levels did not differ between the Reprieve (0.19 ± 0.24 mg/dL) and ODT (0.31 ± 0.39 mg/dL; P = 0.07) groups. Conclusions In this pilot trial, the Reprieve System safely produced significantly faster decongestion compared with ODT. Confirmation of these findings in the ongoing pivotal trial is required. (Fluid Management of Acute Decompensated Heart Failure Subjects Treated With Reprieve Decongestion Management System [DMS] [FASTR]; NCT05174312)

BACKGROUND:Loop diuretics are widely used for managing congestion in patients with heart failure (HF). The TRANSFORM-HF trial is a multicenter randomized study that enrolled heart failure patients, comparing a strategy of torsemide vs furosemide. The time-to-event analysis demonstrated neutral effects on all-cause death at 30 months and the composite of all-cause death and first rehospitalization at 12 months. We evaluated whether a hierarchical win-ratio (WR) framework integrating mortality, recurrent hospitalization, and patient-reported health status provides additional interpretive insight. METHODS:This study is a secondary analysis of the pragmatic, multicenter, open-label, randomized TRANSFORM-HF trial, conducted across 60 US hospitals that randomized 2,859 patients hospitalized with HF to torsemide or furosemide. The primary 12-month hierarchical composite outcome was defined as (1) all-cause mortality, (2) recurrent all-cause hospitalizations, and (3) lack of improvement in the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS). The primary statistical method was a WR analysis adjusting covariates via inverse probability weighting. Subgroup analyses evaluated potential heterogeneity across patient demographics and clinical characteristics. RESULTS:In the primary 12-month intention-to-treat analysis, the adjusted WR was 1.07 (95% CI, 0.98-1.16; P = .13), indicating no significant difference between torsemide and furosemide. A supplementary 30-month analysis with extended mortality follow-up yielded a similar estimate (adjusted WR, 1.06; 95% CI, 0.98-1.16; P = .14); hospitalization and KCCQ-CSS components were assessed through 12 months. As-treated sensitivity analyses were consistent with the neutral primary findings. Exploratory subgroup analyses were not adjusted for multiplicity and should be considered hypothesis-generating. CONCLUSIONS:The overall WR comparison between torsemide and furosemide showed no statistically significant difference in the primary 12-month analysis. The WR framework provided an interpretive decomposition across outcome domains but did not establish superiority of either loop diuretic strategy. All findings should be considered exploratory. TRIAL REGISTRATION:ClinicalTrials.gov, NCT03296813, https://clinicaltrials.gov/study/NCT03296813.

Albuminuria, typically measured by urinary albumin-to-creatinine ratio, is present in nearly half of all patients with heart failure. Even at low levels, albuminuria is a well-established, independent risk marker for incident heart failure and adverse outcomes in those with pre-existing heart failure. Currently, routine urinary albumin-to-creatinine ratio screening is not universally recommended in heart failure guidelines, unlike in guidelines for Type 2 diabetes, chronic kidney disease, and hypertension. Emerging data suggest that this may limit opportunities for early detection, risk stratification, and pharmacologic intervention to improve outcomes. Clinical trials of guideline-directed therapies, including renin-angiotensin inhibitors, sodium-glucose cotransporter 2 inhibitors and finerenone show that reductions in urinary albumin-to-creatinine ratio is associated with risk reductions for cardiovascular, heart failure, and chronic kidney disease outcomes, indicating that albuminuria may function as both a marker of risk and potentially a modifiable factor. This review evaluates the role of albuminuria in predicting heart failure development and progression, its potential as a modifiable risk factor, approaches for measurement, current guideline recommendations for testing, and how heart failure therapies influence albuminuria and associated outcomes.

BACKGROUND:Real-world data regarding diuretic strategies and associated outcomes in patients hospitalized for heart failure (HF) in community health systems are limited. OBJECTIVES:Evaluate associations between initial diuretic therapy, markers of decongestion, and clinical outcomes in patients hospitalized for HF. METHODS:Patients hospitalized for HF from 2015-2022 across 30 health systems in the U.S. were identified in the Truveta national database. High dose loop diuretics were defined as >2.5X home dose or >160 mg IV furosemide equivalent over 24 hours. Four study groups were defined based on most intensive diuretic strategy used within 48 hours of admission: 1) high dose loop diuretics with adjuvant therapy (thiazide or acetazolamide), 2) high dose loop diuretics alone, 3) low dose loop diuretics with adjuvant therapy, and 4) low-dose loop diuretics alone. Multivariable logistic and linear regression models adjusted for clinical and demographic covariates were developed to evaluate associations between initial diuretic strategies and both in-hospital outcomes (acute kidney injury [AKI]), hemoconcentration, and weight change) and the composite of readmission or death. RESULTS:Patients were treated with low dose loop diuretics (N=81,734; 74.9%), high dose loop diuretics (N=17,187; 15.7%), low dose loop diuretics plus adjuvant therapy (N=7,027; 6.4%), and high dose loop diuretics plus adjuvant therapy (N=3,210; 2.9%). Patients treated with more intensive strategies had greater illness severity, including more frequent prior HF hospitalizations and worse kidney function. Adjusted weight loss during hospitalization was greater for patients treated with more intensive strategies (high dose loop with adjuvant: 4.6 lbs [4.0-5.2]; high dose loop alone: 2.1 lbs [1.9-2.4]; low dose loop with adjuvant: 1.4 lbs [1.0-1.8]), as were adjusted odds of AKI. The adjusted odds of 90-day readmission/death were not lower with more intensive initial diuretic strategies. However, odds of 90-day readmission/death were lower for every 5 lbs of achieved weight loss (adjusted odds ratio: 0.97, 95% confidence interval 0.96-0.97). CONCLUSIONS:More intensive diuretic strategies were used in sicker patients, improved in-hospital decongestion, but were not associated with improved 90-day outcomes. However, greater weight loss was associated with modestly lower risk of death or readmission. These data highlight the need for prospective studies to evaluate if enhancing decongestion can improve outcomes in patients hospitalized for HF.