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Aim: To investigate the effects of Cimlanod, a nitroxyl donor with vasodilator properties, on water and salt excretion after an administration of an intravenos bolus of furosemide., Methods and Results: In this randomized, double-blind, mechanistic, crossover trial, 21 patients with left ventricular ejection fraction <45%, increased plasma concentrations of N-terminal pro-B-type natriuretic peptide (NT-proBNP) and receiving loop diuretics were given, on separate study days, either an 8 h intravenous (IV) infusion of cimlanod (12 μg/kg/min) or placebo. Furosemide was given as a 40 mg IV bolus four hours after the start of infusion. The primary endpoint was urine volume in the 4 h after the bolus of furosemide during infusion of cimlanod compared with placebo. Median NT-proBNP at baseline was 1487 (interquartile range: 847-2665) ng/L. Infusion of cimlanod increased cardiac output and reduced blood pressure without affecting cardiac power index consistent with its vasodilator effects. Urine volume in the 4 h post-furosemide was lower with cimlanod (1032 ± 393 ml) versus placebo (1481 ± 560 ml) (p = 0.002), as were total sodium excretion (p = 0.004), fractional sodium excretion (p = 0.016), systolic blood pressure (p < 0.001), estimated glomerular filtration rate (p = 0.012), and haemoglobin (p = 0.010), an index of plasma volume expansion., Conclusions: For patients with heart failure and congestion, vasodilatation with agents such as cimlanod reduces the response to diuretic agents, which may offset any benefit from acute reductions in cardiac preload and afterload., (© 2023 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: For patients with acute heart failure (AHF), substantial diuresis after administration of loop diuretics is generally associated with better clinical outcomes but may cause creatinine to rise, suggesting renal function decline. We investigated the interaction between diuretic response and worsening renal function (WRF) on clinical outcomes in patients with AHF., Methods and Results: In two AHF cohorts (PROTECT, n = 1698 and RELAX-AHF-2, n = 5586 in current analysis), the prognostic impact of WRF (creatinine ≥0.3 mg/dl increase baseline-day 4; sensitivity analyses incorporated baseline renal function) by diuretic response (kg weight loss/40 mg furosemide equivalent baseline-day 4) was investigated with regard to (cardiovascular) death or cardiovascular/renal hospitalization using subpopulation treatment effect pattern plots (STEPP) and survival analyses. WRF occurred in 286 (16.8%) and 1031 (18.5%) patients in PROTECT and RELAX-AHF-2, respectively. Patients with WRF had higher left ventricular ejection fraction and lower estimated glomerular filtration rate at baseline (p < 0.05), and received higher doses of loop diuretics and had a worse diuretic response (p < 0.001). In patients with a poor diuretic response (≤0.35 kg weight loss/40 mg furosemide equivalent as identified by STEPP), WRF was associated with higher risk of (cardiovascular) death or cardiovascular/renal hospitalization (p < 0.001 both cohorts), but this was not the case for patients with a good diuretic response (p = 0.900 both cohorts)., Conclusion: In two large cohorts of patients with AHF, WRF in the first 4 days was not associated with worse outcomes when patients had a good diuretic response. The occurrence of WRF in patients with AHF should therefore be considered in the context of diuretic response., (© 2021 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Objectives: This study sought to characterize the course of decongestion among patients hospitalized for acute heart failure (AHF) by history of atrial fibrillation (AF) and/or atrial flutter (AFL)., Background: AF/AFL and chronic heart failure (HF) commonly coexist. Little is known regarding the impact of AF/AFL on relief of congestion among patients who develop AHF., Methods: We pooled patients from 3 randomized trials of AHF conducted within the Heart Failure Network, the DOSE (Diuretic Optimization Strategies) trial, the ROSE (Renal Optimization Strategies) trial, and the CARRESS-HF (Cardiorenal Rescue Study in Acute Decompensated Heart Failure) trial. The association between history of AF/AFL and in-hospital changes in various metrics of congestion was assessed using covariate-adjusted linear and ordinal logistic regression models., Results: Of 750 unique patients, 418 (56%) had a history of AF/AFL. Left ventricular ejection fraction was higher (35% vs. 27%, respectively; p < 0.001), and N-terminal pro-brain natriuretic peptide (NT-proBNP) levels were nonsignificantly lower at baseline (4,210 pg/ml vs. 5,037 pg/ml, respectively; p = 0.27) in patients with AF/AFL. After adjustment of covariates, history of AF/AFL was associated with less substantial loss of weight (-5.7% vs. -6.5%, respectively; p = 0.02) and decrease in NT-proBNP levels (-18.7% vs. -31.3%, respectively; p = 0.003) by 72 or 96 h. History of AF/AFL was also associated with a blunted increase in global sense of well being at 72 or 96 h (p = 0.04). There was no association between history of AF/AFL and change in orthodema congestion score (p = 0.67) or 60-day composite clinical endpoint (all-cause mortality or any rehospitalization; hazard ratio: 1.21; 95% confidence interval: 0.92 to 1.59; p = 0.17)., Conclusions: More than half of the patients admitted with AHF had a history of AF/AFL. History of AF/AFL was independently associated with a blunted course of in-hospital decongestion. Further research is required to understand the utility of specific therapies targeting AF/AFL during hospitalization for AHF., (Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Though commonly noted in clinical practice, it is unknown if decongestion in acute heart failure (AHF) results in increased serum bicarbonate., Methods and Results: For 678 AHF patients in the DOSE-AHF, CARRESS-HF, and ROSE-AHF trials, we assessed change in bicarbonate (baseline to 72-96 hours) according to decongestion strategy, and the relationship between bicarbonate change and protocol-defined decongestion. Median baseline bicarbonate was 28 mEq/L. Patients with baseline bicarbonate ≥28 mEq/L had lower ejection fraction, worse renal function and higher N-terminal pro-B-type natriuretic peptide than those with baseline bicarbonate <28 mEq/L. There were no differences in bicarbonate change between treatment groups in DOSE-AHF or ROSE-AHF (all P > .1). In CARRESS-HF, bicarbonate increased with pharmacologic care but decreased with ultrafiltration (median +3.3 vs -0.9 mEq/L, respectively; P < .001). Bicarbonate change was not associated with successful decongestion (P > .2 for all trials)., Conclusions: In AHF, serum bicarbonate is most commonly elevated in patients with more severe heart failure. Despite being used in clinical practice as an indicator for decongestion, change in serum bicarbonate was not associated with significant decongestion., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: The ROSE AHF trial (Renal Optimization Strategies Evaluation in Acute Heart Failure) found that when compared with placebo, neither low-dose dopamine (2 µg/kg per minute) nor low-dose nesiritide (0.005 μg/kg per minute without bolus) enhanced decongestion or preserved renal function in AHF patients with renal dysfunction. However, there may be differential responses to vasoactive agents in AHF patients with reduced versus preserved ejection fraction (EF). This post hoc analysis examined potential interaction between treatment effect and EF (EF ≤40% versus >40%) on the ROSE AHF end points., Methods and Results: ROSE AHF enrolled AHF patients (n=360; any EF) with renal dysfunction. The coprimary end points were cumulative urine volume and the change in serum cystatin-C in 72 hours. The effect of dopamine (interaction P=0.001) and nesiritide (interaction P=0.039) on urine volume varied by EF group. In heart failure with reduced EF, urine volume was higher with active treatment versus placebo, whereas in heart failure with preserved EF, urine volume was lower with active treatment. The effect of dopamine and nesiritide on weight change, sodium excretion, and incidence of AHF treatment failure also varied by EF group (interaction P<0.05 for all). There was no interaction between vasoactive treatment's effect and EF on change in cystatin-C. Compared with placebo, dopamine was associated with improved clinical outcomes in heart failure with reduced EF and worse clinical outcomes in heart failure with preserved EF. With nesiritide, there were no differences in clinical outcomes when compared with placebo in both heart failure with reduced EF and heart failure with preserved EF., Conclusions: In this post hoc analysis of ROSE AHF, the response to vasoactive therapies differed in patients with heart failure with reduced EF and heart failure with preserved EF. Investigations of AHF therapies should assess the potential for differential responses in AHF with preserved versus reduced EF., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01132846., (© 2016 American Heart Association, Inc.)

Background: Worsening renal function in heart failure may be related to increased venous congestion, decreased cardiac output, or both. Diuretics are universally used in acute decompensated heart failure, but they may be ineffective and may lead to azotemia. We aimed to compare the decongestive properties of a urine output-guided diuretic adjustment and standard therapy for the management of cardiorenal syndrome in acute decompensated heart failure., Methods and Results: Data were pooled from subjects randomized to the stepwise pharmacologic care algorithm (SPCA) in the CARRESS-HF trial and those who developed cardiorenal syndrome (rise in creatinine >0.3 mg/dL) in the DOSE-AHF and ROSE-AHF trials. Patients treated with SPCA (n = 94) were compared with patients treated with standard decongestive therapy (SDT) that included intravenous loop diuretic use (DOSE-AHF and ROSE-AHF; n = 107) at the time of cardiorenal syndrome and followed for net fluid balance, weight loss, and changing renal function. The SPCA group had higher degrees of jugular venous pressure (P < .0001) at the time of cardiorenal syndrome. The group that received SPCA had more weight change (-3.4 ± 5.2 lb) and more net fluid loss (1.705 ± 1.417 L) after 24 hours than the SDT group (-0.8 ± 3.4 lb and 0.892 ± 1.395 L, respectively; P < .001 for both) with a slight improvement in renal function (creatinine change -0.1 ± 0.3 vs 0.0 ± 0.3 mg/dL, respectively; P = .03)., Conclusions: Compared with SDT, patients who received an intensification of medication therapy for treating persisting congestion had greater net fluid and weight loss without being associated with renal compromise., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Congestion is the most frequent cause for hospitalization in acute decompensated heart failure. Although decongestion is a major goal of acute therapy, it is unclear how the clinical components of congestion (eg, peripheral edema, orthopnea) contribute to outcomes after discharge or how well decongestion is maintained., Methods and Results: A post hoc analysis was performed of 496 patients enrolled in the Diuretic Optimization Strategy Evaluation in Acute Decompensated Heart Failure (DOSE-AHF) and Cardiorenal Rescue Study in Acute Decompensated Heart Failure (CARRESS-HF) trials during hospitalization with acute decompensated heart failure and clinical congestion. A simple orthodema congestion score was generated based on symptoms of orthopnea (≥2 pillows=2 points, <2 pillows=0 points) and peripheral edema (trace=0 points, moderate=1 point, severe=2 points) at baseline, discharge, and 60-day follow-up. Orthodema scores were classified as absent (score of 0), low-grade (score of 1-2), and high-grade (score of 3-4), and the association with death, rehospitalization, or unscheduled medical visits through 60 days was assessed. At baseline, 65% of patients had high-grade orthodema and 35% had low-grade orthodema. At discharge, 52% patients were free from orthodema at discharge (score=0) and these patients had lower 60-day rates of death, rehospitalization, or unscheduled visits (50%) compared with those with low-grade or high-grade orthodema (52% and 68%, respectively; P=0.038). Of the patients without orthodema at discharge, 27% relapsed to low-grade orthodema and 38% to high-grade orthodema at 60-day follow-up., Conclusions: Increased severity of congestion by a simple orthodema assessment is associated with increased morbidity and mortality. Despite intent to relieve congestion, current therapy often fails to relieve orthodema during hospitalization or to prevent recurrence after discharge., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifiers: NCT00608491, NCT00577135., (© 2015 American Heart Association, Inc.)

Aims: We studied the characteristics and clinical outcome related to diuretic response and the effects of serelaxin in patients hospitalized for acute heart failure (AHF)., Methods and Results: RELAX-AHF was a double-blind, placebo-controlled trial, enrolling 1161 patients admitted to hospital for AHF who were randomized to 48 h i.v infusions of placebo or serelaxin (30 µg/kg per day) within 16 h from presentation. Diuretic response was defined as Δ weight kg/[(total i.v. dose)/40 mg] + [(total oral dose)/80 mg)] furosemide (or equivalent loop diuretic dose) up to day 5. Median diuretic response was -0.42 (-1.00, -0.14) kg/40 mg. A poor diuretic response was independently associated with Western-like region (Western Europe, North America, Israel, and Poland), lower diastolic blood pressure, the absence of oedema, higher blood urea nitrogen, and lower levels of aspartate aminotransferase and potassium (all P < 0.01). Randomization to serelaxin was associated with lower doses of i.v. loop diuretics and slightly less weight loss, resulting in a neutral effect on diuretic response. Worse diuretic response was independently associated both with less relief of dyspnoea, measured with a visual analogue scale (VAS) at day 5 (primary endpoint; P = 0.0002), and with a higher risk of cardiovascular death or rehospitalization for heart failure or renal failure through day 60 (secondary endpoint, P < 0.0001), but not with increased 180-day cardiovascular mortality (P = 0.507)., Conclusions: In patients hospitalized for AHF, a poor diuretic response was associated with a poor in-hospital and early post-discharge clinical outcome. Serelaxin had a neutral effect on diuretic response., Trial Registration: NCT00520806., (© 2014 The Authors. European Journal of Heart Failure © 2014 European Society of Cardiology.)

Purpose of Review: Fluid removal and relief of congestion are central to treatment of acute heart failure. Diuretics have been the decongestive mainstay but their known limitations have led to the exploration of alternative strategies. This review compares diuretics with ultrafiltration and examines the recent evidence evaluating their use., Recent Findings: Relevant recent studies are the Diuretic Optimization Strategies Evaluation trial (of diuretics) and the Cardiorenal Rescue Study in Acute Decompensated Heart Failure (of ultrafiltration). The Diuretic Optimization Strategies Evaluation study evaluated strategies of loop diuretic use during acute heart failure (continuous infusion versus intermittent bolus and high dose versus low dose). After 72  h, there was no significant difference with either comparison for the coprimary end points. Patients treated with a high-dose strategy tended to have greater diuresis and more decongestion compared with low-dose therapy, at the cost of transient changes in renal function. The Cardiorenal Rescue Study in Acute Decompensated Heart Failure study showed that in acute heart failure patients with persistent congestion and worsening renal function, ultrafiltration, as compared with a medical therapy, was associated with similar weight loss but greater increase in serum creatinine and more adverse events., Summary: Decongestion remains a major challenge in acute heart failure. Although recent studies provide useful data to guide practice, the relatively poor outcomes point to the continued need to identify better strategies for safe and effective decongestion.

Background: Congestion is a primary driver of symptoms in patients with acute heart failure, and relief of congestion is a critical goal of therapy. Monitoring of response to therapy through the assessment of daily weights and net fluid loss is the current standard of care, yet the relationship between commonly used markers of decongestion and both patient reported symptom relief and clinical outcomes are unknown., Methods and Results: We performed a retrospective analysis of the randomized clinical trial, diuretic optimization strategy evaluation in acute heart failure (DOSE-AHF), enrolling patients hospitalized with a diagnosis of acute decompensated heart failure. We assessed the relationship among 3 markers of decongestion at 72 hours-weight loss, net fluid loss, and percent reduction in serum N terminal B-type natriuretic peptide (NT-proBNP) level-and relief of symptoms as defined by the dyspnea visual analog scale area under the curve. We also determined the relationship between each marker of decongestion and 60-day clinical outcomes defined as time to death, first rehospitalization or emergency department visit. Mean age was 66 years, mean ejection fraction was 35%, and 27% had ejection fraction ≥50%. Of the 3 measures of decongestion assessed, only percent reduction in NT-proBNP was significantly associated with symptom relief (r=0.13; P=0.04). There was no correlation between either weight loss or net fluid loss and symptom relief, (r=0.04; P=0.54 and r=0.07; P=0.27, respectively). Favorable changes in each of the 3 markers of decongestion were associated with improvement in time to death, rehospitalization, or emergency department visit at 60 days (weight: hazard ratio, 0.91; 95% confidence interval, 0.85-0.97 per 4 lbs; weight lost; fluid hazard ratio, 0.94; 95% confidence interval, 0.90-0.99 per 1000 mL fluid loss; NT-proBNP hazard ratio, 0.95; 95% confidence interval, 0.91-0.99 per 10% reduction). These associations were unchanged after multivariable adjustment with the exception that percent reduction in NT-proBNP was no longer a significant predictor (hazard ratio, 0.97; 95% confidence interval, 0.93-1.02). The rates of death, HF hospitalization, or emergency department visit at 60 days for patients with 0, 1, 2, and 3 markers of decongestion (above the median) were 67%, 64%, 46%, and 38%, respectively (log rank P value=0.05)., Conclusions: Weight loss, fluid loss, and NT-proBNP reduction at 72 hours are poorly correlated with dyspnea relief. However, favorable improvements in each of the 3 markers were associated with improved clinical outcomes at 60 days. These data suggest the need for ongoing research to understand the relationships among symptom relief, congestion, and outcomes in patients with acute decompensated heart failure., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. UNIQUE IDENTIFIER: NCT00577135.

Background: Ultrafiltration is an alternative strategy to diuretic therapy for the treatment of patients with acute decompensated heart failure. Little is known about the efficacy and safety of ultrafiltration in patients with acute decompensated heart failure complicated by persistent congestion and worsened renal function., Methods: We randomly assigned a total of 188 patients with acute decompensated heart failure, worsened renal function, and persistent congestion to a strategy of stepped pharmacologic therapy (94 patients) or ultrafiltration (94 patients). The primary end point was the bivariate change from baseline in the serum creatinine level and body weight, as assessed 96 hours after random assignment. Patients were followed for 60 days., Results: Ultrafiltration was inferior to pharmacologic therapy with respect to the bivariate end point of the change in the serum creatinine level and body weight 96 hours after enrollment (P=0.003), owing primarily to an increase in the creatinine level in the ultrafiltration group. At 96 hours, the mean change in the creatinine level was -0.04±0.53 mg per deciliter (-3.5±46.9 μmol per liter) in the pharmacologic-therapy group, as compared with +0.23±0.70 mg per deciliter (20.3±61.9 μmol per liter) in the ultrafiltration group (P=0.003). There was no significant difference in weight loss 96 hours after enrollment between patients in the pharmacologic-therapy group and those in the ultrafiltration group (a loss of 5.5±5.1 kg [12.1±11.3 lb] and 5.7±3.9 kg [12.6±8.5 lb], respectively; P=0.58). A higher percentage of patients in the ultrafiltration group than in the pharmacologic-therapy group had a serious adverse event (72% vs. 57%, P=0.03)., Conclusions: In a randomized trial involving patients hospitalized for acute decompensated heart failure, worsened renal function, and persistent congestion, the use of a stepped pharmacologic-therapy algorithm was superior to a strategy of ultrafiltration for the preservation of renal function at 96 hours, with a similar amount of weight loss with the two approaches. Ultrafiltration was associated with a higher rate of adverse events. (Funded by the National Heart, Lung, and Blood Institute; ClinicalTrials.gov number, NCT00608491.).

Background: Results from the DOSE-AHF study suggest that an initial continuous infusion of loop diuretics is not superior to bolus dosing with regard to clinical endpoints in acute heart failure. We hypothesized that outpatient furosemide dose was associated with congestion and poorer renal function and explored the hypothesis that a continuous infusion may be more effective in patients on higher outpatient diuretic doses., Methods: The DOSE-AHF study randomized 308 patients within 24 hours of admission to high versus low initial intravenous diuretic dose given as either a continuous infusion or bolus. We compared baseline characteristics and assessed associations between mode of administration (bolus vs continuous) and outcomes in patients receiving high-dose (≥120 mg furosemide equivalent, n = 177) versus low-dose (<120 mg furosemide equivalent, n = 131) outpatient diuretics., Results: Patients on higher doses of furosemide were less frequently on renin-angiotensin system inhibitors (P = .01) and had worse renal function and more advanced symptoms. There was a significant interaction between outpatient dose and mode of therapy (P = .01) with respect to net fluid loss at 72 hours after adjusting for creatinine and intensification strategy. Admission diuretic dose was associated with an increased risk of death or rehospitalization at 60 days (adjusted hazard ratio 1.08 per 20-mg increment in dose, 95% CI 1.01-1.16, P = .03)., Conclusions: In acute heart failure, patients on higher diuretic doses have greater disease severity and may benefit from an initial bolus strategy., (Copyright © 2012 Mosby, Inc. All rights reserved.)

Background: Obesity could attenuate diuretic effectiveness in treatment of acute decompensated heart failure (HF)., Methods and Results: The DOSE trial randomized 308 subjects with acute HF to low- versus high-intensification intravenous diuretic therapy. We tested for statistical interactions between obesity and dosing strategy across clinical end points. After 72 hours of treatment, obese subjects (body mass index >30 kg/m(2); n = 173) had greater volume loss than nonobese subjects (n = 119) but similar improvements in dyspnea and freedom from congestion. Both groups had greater fluid loss with high-intensification treatment. Obese subjects had a higher incidence of worsening renal function (WRF) at 72 hours with low-intensification treatment, compared with nonobese subjects. In contrast, nonobese and obese subjects had similar incidence of WRF with high-intensification treatment. There were no differences between obese and nonobese subjects in time to discharge and 60-day freedom from death, emergency department visit, or rehospitalization., Conclusions: The incidence of WRF was greater in obese than in nonobese subjects with low-intensification treatment. However, the frequency of WRF was equivalent in obese and nonobese subjects with high-intensification treatment. Additional studies are needed to assess whether obese patients with acute HF benefit from an initial high-intensification treatment strategy., (Published by Elsevier Inc.)

Background: Loop diuretics are an essential component of therapy for patients with acute decompensated heart failure, but there are few prospective data to guide their use., Methods: In a prospective, double-blind, randomized trial, we assigned 308 patients with acute decompensated heart failure to receive furosemide administered intravenously by means of either a bolus every 12 hours or continuous infusion and at either a low dose (equivalent to the patient's previous oral dose) or a high dose (2.5 times the previous oral dose). The protocol allowed specified dose adjustments after 48 hours. The coprimary end points were patients' global assessment of symptoms, quantified as the area under the curve (AUC) of the score on a visual-analogue scale over the course of 72 hours, and the change in the serum creatinine level from baseline to 72 hours., Results: In the comparison of bolus with continuous infusion, there was no significant difference in patients' global assessment of symptoms (mean AUC, 4236±1440 and 4373±1404, respectively; P=0.47) or in the mean change in the creatinine level (0.05±0.3 mg per deciliter [4.4±26.5 μmol per liter] and 0.07±0.3 mg per deciliter [6.2±26.5 μmol per liter], respectively; P=0.45). In the comparison of the high-dose strategy with the low-dose strategy, there was a nonsignificant trend toward greater improvement in patients' global assessment of symptoms in the high-dose group (mean AUC, 4430±1401 vs. 4171±1436; P=0.06). There was no significant difference between these groups in the mean change in the creatinine level (0.08±0.3 mg per deciliter [7.1±26.5 μmol per liter] with the high-dose strategy and 0.04±0.3 mg per deciliter [3.5±26.5 μmol per liter] with the low-dose strategy, P=0.21). The high-dose strategy was associated with greater diuresis and more favorable outcomes in some secondary measures but also with transient worsening of renal function., Conclusions: Among patients with acute decompensated heart failure, there were no significant differences in patients' global assessment of symptoms or in the change in renal function when diuretic therapy was administered by bolus as compared with continuous infusion or at a high dose as compared with a low dose. (Funded by the National Heart, Lung, and Blood Institute; ClinicalTrials.gov number, NCT00577135.).

Many of the primary clinical manifestations of heart failure are due to fluid retention and congestion, and therefore treatments targeting congestion play a central role in heart failure management. Diuretic therapy remains the cornerstone of congestion treatment, and diuretics are prescribed to the majority of heart failure patients. Despite this ubiquitous use, there is limited evidence from prospective randomized studies to guide the use of diuretics. Some observational data have suggested that diuretics may actually be harmful in heart failure, potentially contributing to worsening renal function, neurohormonal activation, and even heart failure progression. Recent clinical trial data have provided new insights into the balance of risks and benefits from diuretics. This review describes the mechanism of action of available diuretic classes, reviews their clinical use based on current guidelines, and briefly discusses evolving alternatives to diuretic therapy in the management of congestion in heart failure patients.

Background: Decongestion is a primary goal during hospitalizations for decompensated heart failure (HF). However, data surrounding the preferred route and strategy of diuretic administration are limited with varying results in prior studies.Methods: This is a retrospective analysis using patients from ASCEND-HF with a stable diuretic strategy in the first 24 hours following randomization. Patients were divided into three groups: intravenous (IV) continuous, IV bolus and oral strategy. Baseline characteristics, in-hospital outcomes, 30-day composite cardiovascular mortality or HF rehospitalization and 180-day all-cause mortality were compared across groups. Inverse propensity weighted modeling was used for adjustment.Results: Among 5,738 patients with a stable diuretic regimen in the first 24 hours (80% of overall ASCEND trial), 3,944 (68.7%) patients received IV intermittent bolus administration of diuretics, 799 (13.9%) patients received IV continuous therapy and 995 (17.3%) patients with oral administration. Patients in the IV continuous group had a higher baseline creatinine (IV continuous 1.4 [1.1-1.7]; intermittent bolus 1.2 [1.0-1.6]; oral 1.2 [1.0-1.4] mg/dL; P <0.001) and high NTproBNP (IV continuous 5,216 [2,599-11,603]; intermittent bolus 4,944 [2,339-9,970]; oral 3,344 [1,570-7,077] pg/mL; P <0.001). There was no difference between IV continuous and intermittent bolus group in weight change, total urine output and change in renal function till 10 days/discharge (adjusted P >0.05 for all). There was no difference in 30 day mortality and HF readmission (adjusted OR 1.08 [95%CI: 0.74, 1.57]; P = 0.701) and 180 days mortality (adjusted OR 1.04 [95%CI: 0.75, 1.43]; P = 0.832).Conclusion: In a large cohort of patients with decompensated HF, there were no significant differences in diuretic-related in-hospital, or post-discharge outcomes between IV continuous and intermittent bolus administration. Tailoring appropriate diuretic strategy to different states of acute HF and congestion phenotypes needs to be further investigated. [ABSTRACT FROM AUTHOR]

B This article refers to 'Association of time-to-intravenous furosemide with mortality in acute heart failure: data from REPORT-HF' by W. Ouwerkerk I et al i ., published in this issue on pages 43-51. b There are acute cardiovascular conditions in which the speed of treatment is directly correlated with clinical outcomes - most notably, in ST-elevation myocardial infarction ("door-to-balloon time") and in cardiac arrest (time to defibrillation). Early intravenous heart failure therapy and outcomes among older patients hospitalized for acute decompensated heart failure: findings from the Acute Decompensated Heart Failure Registry Emergency Module (ADHERE-EM). Patients in whom an AHF diagnosis is more apparent (thus allowing for prompter treatment) may have an inherently more favourable long-term prognosis than patients with greater diagnostic complexity (resulting in delayed first diuretic doses). [Extracted from the article]

Background-In-hospital worsening heart failure (WHF) is an important event that has inconsistent definitions used across trials. We used data from 2 acute heart failure (HF) trials from the National Institutes of Health HF Network, DOSE (Diuretic Optimization Strategies Evaluation) and ROSE (Renal Optimization Strategies), to understand event rates associated with different WHF definitions. Methods and Results-We pooled data from 668 patients in DOSE and ROSE and assessed the relationship between WHF and the composite end point of rehospitalization, emergency room visits for HF, and mortality through 60 days. We also assessed for a differential relationship between the timing of WHF development and outcomes. The overall incidence of WHF was 14.6% (24.1% in DOSE, 6.3% in ROSE, and 5.0% in DOSE using the ROSE definition). WHF was associated with an increase in the composite end point (hazard ratio [HR], 1.64; 95% confidence interval [CI], 1.11-2.42; P=0.01). However, the association between WHF and outcomes was significantly stronger in ROSE than in DOSE (HR, 2.67; 95% CI, 1.45-4.91; P<0.01 and HR, 1.28; 95% CI, 0.79-2.08; P=0.31, respectively). Development of WHF between baseline to 24 hours compared with 24 to 48 hours or 48 to 72 hours demonstrated a trend toward improved outcomes (HR, 0.49; 95% CI, 0.21-1.17; P=0.11 and HR, 0.45; 95% CI, 0.20-1.04; P=0.06, respectively). Conclusions-A WHF definition that excluded the intensification of diuretics resulted in a lower event rate but a stronger association with outcomes. These data support the need for continued efforts to standardize WHF definitions in clinical trials. [ABSTRACT FROM AUTHOR]

Management approaches for patients in the emergency department ( ED) who present with acute heart failure ( AHF) have largely focused on intravenous diuretics. Yet, the primary pathophysiologic derangement underlying AHF in many patients is not solely volume overload. Patients with hypertensive AHF (H- AHF) represent a clinical phenotype with distinct pathophysiologic mechanisms that result in elevated ventricular filling pressures. To optimize treatment response and minimize adverse events in this subgroup, we propose that clinical management be tailored to a conceptual model of disease that is based on these mechanisms. This consensus statement reviews the relevant pathophysiology, clinical characteristics, approach to therapy, and considerations for clinical trials in ED patients with H- AHF. [ABSTRACT FROM AUTHOR]

Following those important results, how should we manage loop diuretics in HF patients without clinical congestion and low dose of loop diuretics? 6 Dauw J, Martens P, Tersalvi G, Schouteden J, Deferm S, Gruwez H, De Moor B, Nijst P, Dupont M, Mullens W. Diuretic response and effects of diuretic omission in ambulatory heart failure patients on chronic low-dose loop diuretic therapy. Although diuretic discontinuation may be feasible in carefully selected patients, chronic loop diuretics are central to maintaining sodium and fluid balance in many patients with chronic HF. [Extracted from the article]

Congestion and volume overload are the hallmarks of acute decompensated heart failure (ADHF), and loop diuretics have historically been the cornerstone of treatment. The demonstrated efficacy of loop diuretics in managing congestion is balanced by the recognized limitations of diuretic resistance, neurohormonal activation, and worsening renal function. However, the recently published DOSE (Diuretic Optimization Strategies Evaluation) trial suggests that previous concerns about the safety of high-dose diuretics may not be valid. There has been a growing interest in alternative strategies to manage volume retention in ADHF with improved efficacy and safety profiles. Peripheral venovenous ultrafiltration (UF) represents a potentially promising approach to volume management in ADHF. Small studies suggest that UF may allow for more effective fluid removal compared with diuretics, with improved quality of life and reduced rehospitalization rates. However, further investigation is needed to completely define the role of UF in patients with ADHF. This review summarizes available data on the use of both diuretics and UF in ADHF patients and identifies challenges and unresolved questions for each approach. [Copyright &y& Elsevier]

Congest Heart Fail. 2010;16(4)(suppl 1):S68–S72. ©2010 Wiley Periodicals, Inc. Many of the primary clinical manifestations of heart failure are due to fluid retention and congestion, and therefore treatments targeting congestion play a central role in heart failure management. Diuretic therapy remains the cornerstone of congestion treatment, and diuretics are prescribed to the majority of heart failure patients. Despite this ubiquitous use, there is limited evidence from prospective randomized studies to guide the use of diuretics. Some observational data have suggested that diuretics may actually be harmful in heart failure, potentially contributing to worsening renal function, neurohormonal activation, and even heart failure progression. Recent clinical trial data have provided new insights into the balance of risks and benefits from diuretics. This review describes the mechanism of action of available diuretic classes, reviews their clinical use based on current guidelines, and briefly discusses evolving alternatives to diuretic therapy in the management of congestion in heart failure patients. [ABSTRACT FROM AUTHOR]

The article discusses the efficacy and safety of loop diuretics in treating acute decompensated heart failure (ADHF) in the U.S. The article states that ADHF has evolved as an essential clinical syndromes in the country due to its high incidence of morbidity and medical costs. It also notes that loop diuretics poses properties that maintains the safety and effectiveness of the treatment supported by different clinical studies.

Supplemental Digital Content is available in the text. Background: Black patients have higher rates of hospitalization for acute heart failure than other race/ethnic groups. We sought to determine whether diuretic efficiency is associated with racial differences in risk for rehospitalization after acute heart failure. Methods: A post hoc analysis was performed on 721 subjects (age, 68±13 years; 22% black) enrolled in 3 acute heart failure clinical trials: ROSE-AHF (Renal Optimization Strategies Evaluation in Acute Heart Failure), DOSE-AHF (Diuretic Optimization Strategy Evaluation in Acute Decompensated Heart Failure), and CARRESS-HF (Cardiorenal Rescue Study in Acute Decompensated Heart Failure). Repeated-measures ANOVA was used to test for a race×time effect on measures of decongestion. Diuretic efficiency was calculated as net fluid balance per total furosemide equivalents. In a subset of subjects, Cox regression was used to examine the association between race and rehospitalization according to plasma renin activity (PRA). Results: Compared with nonblack patients, black patients were younger and more likely to have nonischemic heart failure. During the first 72 to 96 hours, there was greater fluid loss (P =0.001), decrease in NT-proBNP (N-terminal pro-B-type natriuretic peptide; P =0.002), and lower levels of PRA (P <0.0001) in black patients. Diuretic efficiency was higher in black than in nonblack patients (403 [interquartile range, 221–795] versus 325 [interquartile range, 154–698]; P =0.014). However, adjustment for baseline PRA attenuated the association between black race and diuretic efficiency. Over a median follow-up of 68 (interquartile range, 56–177) days, there was an increased risk of all-cause and heart failure–specific rehospitalization in nonblack patients with increasing levels of PRA, while the risk of rehospitalization was relatively constant across levels of PRA in black patients. Conclusions: Higher diuretic efficiency in black patients with acute heart failure may be related to racial differences in activity of the renin-angiotensin-aldosterone system. [ABSTRACT FROM AUTHOR]

Introduction: In the ATHENA-HF trial, addition of high-dose spironolactone to standard care did not improve congestion among acute heart failure (HF) patients with a broad range of renal function. Patients with renal insufficiency and other risk factors for diuretic resistance may be most likely to derive benefits from high-dose spironolactone. Methods: The ATHENA-HF trial randomized 360 acute HF (AHF) patients with glomerular filtration rate (GFR) ≥ 30 mL/min/1.732 to spironolactone 100 mg daily or usual care (i.e., spironolactone 25 mg daily if previously taking spironolactone, or placebo) for 96 hours. The primary endpoint was change in log N-terminal pro-B-type natriuretic peptide (NT-proBNP) during the treatment period. Effects of study therapy within GFR tertiles and subgroups at risk for diuretic resistance (lower blood pressure, diabetes mellitus [DM], higher loop diuretic dose) were assessed. Results: Median GFR by tertile was 44, 60, and 87 mL/min/1.732. Across tertiles, there was no benefit of high-dose spironolactone on any efficacy endpoint, including changes in log NT-proBNP, body weight, and clinical congestion score (all interaction p ≥0.06). High-dose spironolactone had a no significant effect on NT-proBNP reduction regardless of blood pressure, DM status, and baseline loop diuretic dose (Figure). In-hospital changes in potassium and creatinine were similar between treatment groups for all GFR tertiles (all p for interaction ≥0.18). 60-day mortality rates were numerically higher among patients in lower GFR tertiles, but relative effects of study treatment did not differ by renal function (interaction p =0.64). Conclusions: High-dose spironolactone did not improve congestion over usual care among AHF patients, irrespective of renal function and risk factors for diuretic resistance. In-hospital initiation or continuation of spironolactone was safe, even when administered at high doses to patients with moderate renal dysfunction. [ABSTRACT FROM AUTHOR]

Background: Worsening renal function (WRF) in the setting of aggressive diuresis for acute heart failure treatment may reflect renal tubular injury or simply indicate a hemodynamic or functional change in glomerular filtration. Well-validated tubular injury biomarkers, N-acetyl-β-d-glucosaminidase, neutrophil gelatinase-associated lipocalin, and kidney injury molecule 1, are now available that can quantify the degree of renal tubular injury. The ROSE-AHF trial (Renal Optimization Strategies Evaluation-Acute Heart Failure) provides an experimental platform for the study of mechanisms of WRF during aggressive diuresis for acute heart failure because the ROSE-AHF protocol dictated high-dose loop diuretic therapy in all patients. We sought to determine whether tubular injury biomarkers are associated with WRF in the setting of aggressive diuresis and its association with prognosis.Methods: Patients in the multicenter ROSE-AHF trial with baseline and 72-hour urine tubular injury biomarkers were analyzed (n=283). WRF was defined as a ≥20% decrease in glomerular filtration rate estimated with cystatin C.Results: Consistent with protocol-driven aggressive dosing of loop diuretics, participants received a median 560 mg IV furosemide equivalents (interquartile range, 300-815 mg), which induced a urine output of 8425 mL (interquartile range, 6341-10 528 mL) over the 72-hour intervention period. Levels of N-acetyl-β-d-glucosaminidase and kidney injury molecule 1 did not change with aggressive diuresis (both P>0.59), whereas levels of neutrophil gelatinase-associated lipocalin decreased slightly (-8.7 ng/mg; interquartile range, -169 to 35 ng/mg; P<0.001). WRF occurred in 21.2% of the population and was not associated with an increase in any marker of renal tubular injury: neutrophil gelatinase-associated lipocalin (P=0.21), N-acetyl-β-d-glucosaminidase (P=0.46), or kidney injury molecule 1 (P=0.22). Increases in neutrophil gelatinase-associated lipocalin, N-acetyl-β-d-glucosaminidase, and kidney injury molecule 1 were paradoxically associated with improved survival (adjusted hazard ratio, 0.80 per 10 percentile increase; 95% confidence interval, 0.69-0.91; P=0.001).Conclusions: Kidney tubular injury does not appear to have an association with WRF in the context of aggressive diuresis of patients with acute heart failure. These findings reinforce the notion that the small to moderate deteriorations in renal function commonly encountered with aggressive diuresis are dissimilar from traditional causes of acute kidney injury. [ABSTRACT FROM AUTHOR]

Background: Oxidative stress may contribute to heart failure (HF) progression. Inhibiting xanthine oxidase in hyperuricemic HF patients may improve outcomes.Methods and Results: We randomly assigned 253 patients with symptomatic HF, left ventricular ejection fraction ≤40%, and serum uric acid levels ≥9.5 mg/dL to receive allopurinol (target dose, 600 mg daily) or placebo in a double-blind, multicenter trial. The primary composite end point at 24 weeks was based on survival, worsening HF, and patient global assessment. Secondary end points included change in quality of life, submaximal exercise capacity, and left ventricular ejection fraction. Uric acid levels were significantly reduced with allopurinol in comparison with placebo (treatment difference, -4.2 [-4.9, -3.5] mg/dL and -3.5 [-4.2, -2.7] mg/dL at 12 and 24 weeks, respectively, both P<0.0001). At 24 weeks, there was no significant difference in clinical status between the allopurinol- and placebo-treated patients (worsened 45% versus 46%, unchanged 42% versus 34%, improved 13% versus 19%, respectively; P=0.68). At 12 and 24 weeks, there was no significant difference in change in Kansas City Cardiomyopathy Questionnaire scores or 6-minute walk distances between the 2 groups. At 24 weeks, left ventricular ejection fraction did not change in either group or between groups. Rash occurred more frequently with allopurinol (10% versus 2%, P=0.01), but there was no difference in serious adverse event rates between the groups (20% versus 15%, P=0.36).Conclusions: In high-risk HF patients with reduced ejection fraction and elevated uric acid levels, xanthine oxidase inhibition with allopurinol failed to improve clinical status, exercise capacity, quality of life, or left ventricular ejection fraction at 24 weeks.Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00987415. [ABSTRACT FROM AUTHOR]

Introduction: Atrial fibrillation/atrial flutter (AF/AFL) and chronic heart failure (HF) commonly coexist. However, little is known regarding the impact of AF/AFL among patients who develop acute HF (AHF). We aimed to characterize the course of decongestion among patients hospitalized for AHF by AF/AFL history. Methods: We pooled patients from 3 randomized AHF trials conducted within the Heart Failure Network (DOSE, ROSE, and the diuretic arm of CARRESS-HF). The association of AF/AFL history and in-hospital changes in various metrics of congestion at the completion of the study period was assessed using covariate-adjusted linear regression models. Results: Of 750 patients, 418 (56%) had a history of AF/AFL. Left ventricular ejection fraction was higher (35% vs. 27%, P<0.001) and N-terminal pro-brain natriuretic peptide (NT-proBNP) levels were lower at baseline (4210 pg/mL vs. 5037 pg/mL, P=0.27) in AF/AFL. After covariate adjustment, history of AF/AFL was associated with less weight loss (-4% vs. -5%, P=0.02) and less reduction in NT-proBNP levels (-34% vs. -46%, P= 0.003) by 72/96 hours. Comprehensive trends in weight and NT-proBNP are displayed in the Figure. History of AF/AFL was also associated with a blunted increase in global sense of well-being at 72/96 hours (P=0.012). There was no association between AF/AFL history and change in orthodema congestion score (P=0.7) or the 60-day composite clinical endpoint (all-cause mortality, rehospitalization, or emergency room visit; 43% vs. 42%, P=0.3). Conclusions: History of AF/AFL was present in over half of patients admitted with AHF and was independently associated with a blunted course of decongestion. Further research is required to determine whether targeting AF/AFL will reduce hospital resource utilization and length of stay in AHF. [ABSTRACT FROM AUTHOR]