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BACKGROUND: Worsening renal function (WRF) portends a poor prognosis, and recent deterioration in creatinine might identify patients with elevated intrarenal adenosine in whom adenosine A(1) antagonism may improve renal hemodynamics and function. The purpose of this pilot study was to assess whether rolofylline, an adenosine A(1) antagonist (A(1)RA), would facilitate diuresis while maintaining renal function in patients with acutely decompensated heart failure (ADHF) and recent WRF. METHODS AND RESULTS: Seventy-six patients with ADHF, volume overload, and recent renal deterioration received rolofylline (30 mg, n = 36) or placebo (n = 40) for 3 days. Rolofylline did not demonstrate a beneficial effect on the primary end points of worsening heart failure or renal function after admission or death or readmission within 30 days. Similar proportions of patients receiving rolofylline (33%) and placebo (30%) were treatment failures within 30 days. However, persistent renal impairment (through Day 14) tended to be less common with rolofylline (6%) than placebo (18%). At Day 14, 11 patients receiving placebo and 13 patients receiving rolofylline had a decrease in creatinine > or = 0.3 mg/dL. There were fewer heart failure readmissions with rolofylline (n = 2) than with placebo (n = 7) through Day 60. CONCLUSIONS: The Placebo-Controlled Study of the Effects of KW-3902 Injectable Emulsion on Heart Failure Signs and Symptoms, Diuresis, Renal Function, and Clinical Outcomes in Subjects Hospitalized with Worsening Renal Function and Heart Failure Requiring Intravenous Therapy (ie, REACH UP) study did not demonstrate any clear benefit of rolofylline in patients with ADHF and worsening renal function. However, beneficial trends raise the possibility that A(1)RAs might prevent renal dysfunction in these high risk patients. To test this hypothesis, further larger studies need to evaluate the effects of adenosine A(1) antagonists in patients with progressive renal dysfunction in the face of active heart failure therapy. [ABSTRACT FROM AUTHOR]

Background: Palliative care (PC) in advanced heart failure (HF) aims to improve symptoms and quality of life (QOL), in part through medication management. The impact of PC on polypharmacy (>5 medications) remains unknown., Methods and Results: We explored patterns of polypharmacy in the Palliative Care in HF (PAL-HF) randomized controlled trial of standard care vs interdisciplinary PC in advanced HF (N = 150). We describe differences in medication counts between arms at 2, 6, 12, and 24 weeks for HF (12 classes) and PC (6 classes) medications. General linear mixed models were used to evaluate associations between treatment arm and polypharmacy over time. The median age of the patients was 72 years (interquartile range 62-80 years), 47% were female, and 41% were Black. Overall, 48% had ischemic etiology, and 55% had an ejection fraction of 40% or less. Polypharmacy was present at baseline in 100% of patients. HF and PC medication counts increased in both arms, with no significant differences in counts by drug class at any time point between arms., Conclusions: In a trial of patients with advanced HF considered eligible for PC, polypharmacy was universal at baseline and increased during follow-up with no effect of the palliative intervention on medication counts relative to standard care., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: In a randomized control trial, Palliative Care in Heart Failure (PAL-HF) improved heart failure-related quality of life, though cost-effectiveness remains unknown. The aim of this study was to evaluate the cost-effectiveness of the PAL-HF trial, which provided outpatient palliative care to patients with advanced heart failure., Methods and Results: Outcomes for usual care and PAL-HF strategies were compared using a Markov cohort model over 36 months from a payer perspective. The model parameters were informed by PAL-HF trial data and supplemented with meta-analyses and Medicare administrative data. Outcomes included hospitalization, place of death, Medicare expenditures, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios. Simulated mortality rates were the same for PAL-HF and usual care cohorts, at 89.7% at 36 months. In the base case analysis, the PAL-HF intervention resulted in an incremental gain of 0.03 QALYs and an incremental cost of $964 per patient for an incremental cost-effectiveness ratio of $29,041 per QALY. In 1-way sensitivity analyses, an intervention cost of up to $140 per month is cost effective at $50,000 per QALY. Of 1000 simulations, the PC intervention had a 66.1% probability of being cost effective at a $50,000 willingness-to-pay threshold assuming no decrease in hospitalization. In a scenario analysis, PAL-HF decreased payer spending through reductions in noncardiovascular hospitalizations., Conclusions: These results from this single-center trial are encouraging that palliative care for advanced heart failure is an economically attractive intervention. Confirmation of these findings in larger multicenter trials will be an important part of developing the evidence to support more widespread implementation of the PAL-HF palliative care intervention., (Published by Elsevier Inc.)

Background: The inflammatory cytokine IL-6 has been previously implicated in the pathophysiology of acute decompensated heart failure (HF). Prior observations in acute HF patients have suggested that IL-6 may be associated with outcomes and modulated by nesiritide. We aimed to evaluate the associations between serial IL-6 measurements, mortality and rehospitalization in acute HF., Methods and Results: We analyzed the associations between IL-6 in acute HF, readmission, and mortality (30 and 180 days) using a cohort of 883 hospitalized patients from the ASCEND-HF trial (nesiritide vs placebo). Plasma IL-6 was measured at randomization (baseline), 48-72 hours, and 30 days. The median IL-6 was highest at baseline (14.1 pg/mL) and decreased at subsequent time points (7.6 pg/mL at 30 days). In a univariable Cox regression analysis, the baseline IL-6 was associated with 30- and 180-day mortality (hazard ratio per log 1.74, 95% confidence interval 1.09-2.78, P = .021; hazard ratio 3.23, confidence interval 1.18-8.86, P = .022, respectively). However, there was no association after multivariable adjustment. IL-6 at 48-72 hours was found to be independently associated with 30-day mortality (hazard ratio 8.2, confidence interval 1.2-57.5, P= .03), but not 180-day mortality in multivariable analysis that included the ASCEND-HF risk model and amino terminal pro-B-type natriuretic peptide as covariates. In comparison with placebo, nesiritide therapy was not associated with differences in serial IL-6 levels., Conclusions: Although elevated IL-6 levels were associated with higher all-cause mortality in acute HF, no independent association with this outcome was identified at baseline or 30-day measurements. In contrast with prior reports, we did not observe any impact of nesiritide over placebo on serial IL-6 levels., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Amino-terminal pro-B-type natriuretic peptide (NTproBNP) is closely associated with prognosis in acute decompensated heart failure (ADHF). As a result, there has been great interest measuring it during the course of treatment. The prognostic implications in both short-term and follow-up changes in NTproBNP need further clarification., Methods: Baseline, 48-72 hour, and 30-day NTproBNP levels were measured in 795 subjects in the ASCEND-HF trial. Multivariable logistic and Cox-proportional hazards models were used to test the association between static, relative, and absolute changes in NTproBNP with outcomes during and after ADHF., Results: The median NTproBNP at baseline was 5773 (2981-11,579) pg/mL; at 48-72 hours was 3036 (1191-6479) pg/mL; and at 30 days was 2914 (1364-6667) pg/mL. Absolute changes in NTproBNP by 48-72 hours were not associated with 30-day heart failure rehospitalization or mortality (P = .065), relative changes in NTproBNP were nominally associated (P = .046). In contrast, both absolute and relative changes in NTproBNP from baseline to 48-72 hours and to 30 days were closely associated with 180-day mortality (P < .02 for all) with increased discrimination compared to the multivariable models with baseline NTproBNP (P <.05 for models with relative and absolute change at both time points)., Conclusions: Although the degree of absolute change in NTproBNP was dependent on baseline levels, both short-term absolute and relative changes in NTproBNP were independently and incrementally associated with long-term clinical outcomes. Changes in NTproBNP levels at 30-days were particularly well associated with long-term clinical outcomes., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The prevalence of heart failure continues to grow, and this is accompanied by an increase in hospitalization for acute heart failure. Hospitalization for heart failure results in a trajectory shift of the syndrome and is associated with worsening outcomes, increased mortality risk, and high costs. Numerous clinical trials over the past 2 decades have had limited success, with no single agent shown to improve mortality risk. The lack of success is multifactorial and in part related to inadequate targets and end points selected for intervention, underscoring the need to better understand and define the pathophysiology of acute heart failure. To better inform future drug development, this review critically explores the short-term end points and outcomes that previous phase III acute heart failure trials have examined., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Circulating cardiac troponin levels (cTn), representative of myocardial injury, are commonly elevated in heart failure (HF) and related to adverse clinical events. However, whether cTn represents a spectrum of risk in HF is unclear., Methods: Baseline, 48-72-hour, and 30-day plasma cTnI was measured with the use of a new highly sensitive assay in 900 subjects with acute decompensated HF (ADHF) in ASCEND-HF. Multivariable models determined the relationship between cTnI and outcomes., Results: The median (interquartile range) cTnI was 16.4 (9.3-31.6) ng/L at baseline, 14.1 (7.8-29.7) ng/L at 48-72 hours, and 11.6 (6.8-22.5) ng/L at 30 days. After additional adjustment for N-terminal pro-B-type natriuretic peptide (NT-proBNP) to established risk predictors, both baseline (odds ratio [OR] 1.25; P = .03) and 48-72-hour (OR 1.43; P = .001) cTnI were associated with higher risk for death or worsening HF before discharge. However, only cTnI at 30 days was associated with 180-day death (hazard ratio 1.25; P = .007). There were no curvilinear associations between changing cTnI and clinical outcomes., Conclusions: Circulating cTnI level was associated with clinical outcomes in ADHF, but these observations diminished with additional adjustment for NT-proBNP. Although they likely represent a spectrum of risk in ADHF, these findings question the implications of changing cTnI levels during treatment., (Copyright © 2018. Published by Elsevier Inc.)

Background: Hospitalization for acute decompensated heart failure (ADHF) is associated with a high postdischarge mortality and readmission rate. The association between baseline blood urea nitrogen (BUN) and clinical outcomes in patients admitted for ADHF was evaluated in a post-hoc analysis of the ACTIV in CHF trial., Methods and Results: Patients were categorized into quartiles according to baseline BUN. Cox proportional hazards regression was used to test the association between BUN, mortality, and death or readmission within 60 days. Patients in the highest quartile (>40 mg/dL) had the highest 60-day mortality (14.3%, 9.3%, 4.0%, 0%, respectively; P < .001) and the highest rate of death or heart failure hospitalization (30.0%, 21.3% 18.4%, 8.6%; P < .001). After adjustment for covariates, BUN was a statistically significant predictor of both mortality and the composite endpoint of death or heart failure hospitalization at 60 days after hospital discharge. Serum creatinine and estimated creatinine clearance did not predict mortality after covariate adjustment., Conclusions: Higher baseline BUN is a powerful predictor of increased postdischarge mortality in patients hospitalized for heart failure, even in the absence of severe renal failure. Even mild to moderate elevations in baseline BUN were predictive. BUN remains an easily accessible risk stratification tool that physicians should closely monitor in the hospital setting.

Background: Classifying patients with advanced congestive heart failure (CHF) by baseline measures of congestion and perfusion has been used to estimate hemodynamic status and to select and titrate therapy. We describe clinical characteristics of 4 hemodynamic profiles-wet/cold, wet/warm, dry/cold, and dry/warm-in patients with advanced CHF and assess relations between symptoms, physical signs, and outcomes with each profile., Methods and Results: We retrospectively assessed baseline symptoms, physical-examination variables, and 1-year outcomes of 440 patients in a randomized trial. With univariable and multivariable logistic regression, we examined relations of physical-examination variables to hemodynamic profiles. We also assessed the rates of death and death or readmission by profile. Severity of CHF symptoms did not predict the wet-versus-dry profile or cold-versus-warm status, despite significant differences in hemodynamics among groups. Of the physical-examination variables, only a lower proportional pulse pressure was a significant multivariable predictor of the wet category. Among wet patients (n = 348), this same variable was the only significant multivariable predictor of the cold category. For dry patients (n = 92), the cold category was predicted in multivariable analysis by supine heart rate and hepatomegaly. Survival was similar among profiles: wet/cold, 54.2% (n = 91); wet/warm, 58.3% (n = 105); dry/cold, 78.9% (n = 15); and dry/warm, 67.1%, P =.13 (n = 49). Event-free survival also was similar among profiles: wet/cold, 22.0% (n = 37); wet/warm, 29.4% (n = 53); dry/cold, 42.1% (n = 8); and dry/warm, 31.5%, P =.44 (n = 23)., Conclusions: The patient's history and physical examination alone may lead to inaccurate estimation of hemodynamic status and thus suboptimal management for patients with advanced CHF.