Loop diuretic therapy in heart failure: the need for solid evidence on a fluid issue.
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ABSTRACT: Background
Heart failure (HF) is a common condition associated with substantial cost, morbidity, and mortality. Because results of clinical trials in the acute decompensated heart failure (ADHF) setting have been mostly neutral, loop diuretics remain the mainstay of treatment.Hypothesis
Loop diuretic use may be associated with unfavorable outcomes.Methods
A MEDLINE literature search was performed to identify articles relating to heart failure and loop diuretics. The current evidence on the risks and benefits of loop diuretics for the treatment of ADHF is reviewed.Results
Loop diuretics are associated with symptomatic improvements in congestion, urine output, and body weight, but have shown no long-term mortality benefit. Loop diuretics, especially at high doses, are associated with worsened renal function and other poor outcomes.Conclusions
Loop diuretics still prove useful in HF treatment, but risk-benefit analysis of these agents in the treatment of ADHF requires a well-designed prospective study.
SUBMITTER: Chiong JR
PROVIDER: S-EPMC6653669 | biostudies-literature | 2010 Jun
REPOSITORIES: biostudies-literature
Publications
Loop diuretic therapy in heart failure: the need for solid evidence on a fluid issue.
Chiong Jun R JR Cheung Rebecca J RJ
Clinical cardiology 20100601 6
<h4>Background</h4>Heart failure (HF) is a common condition associated with substantial cost, morbidity, and mortality. Because results of clinical trials in the acute decompensated heart failure (ADHF) setting have been mostly neutral, loop diuretics remain the mainstay of treatment.<h4>Hypothesis</h4>Loop diuretic use may be associated with unfavorable outcomes.<h4>Methods</h4>A MEDLINE literature search was performed to identify articles relating to heart failure and loop diuretics. The curre ...[more]
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Project description:ObjectivesThis study compared combination diuretic strategies in acute heart failure (AHF) complicated by diuretic resistance (DR).BackgroundCombination diuretic regimens to overcome loop DR are commonly used but with limited evidence.MethodsThis study was a randomized, double-blinded trial in 60 patients hospitalized with AHF and intravenous (IV) loop DR. Patients were randomized to oral metolazone, IV chlorothiazide, or tolvaptan therapy. All patients received concomitant high-dose IV infusions of furosemide. The primary outcome was 48-h weight loss.ResultsThe cohort exhibited DR prior to enrollment, producing 1,188 ± 476 ml of urine in 12 h during high-dose loop diuretic therapy (IV furosemide: 612 ± 439 mg/day). All 3 interventions significantly improved diuretic efficacy (p < 0.001). Compared to metolazone (4.6 ± 2.7 kg), neither IV chlorothiazide (5.8 ± 2.7 kg; 1.2 kg [95% confidence interval (CI)]: -2.9 to 0.6; p = 0.292) nor tolvaptan (4.1 ± 3.3 kg; 0.5 kg [95% CI: -1.5 to 2.4; p = 0.456) resulted in more weight loss at 48 h. Median (interquartile range [IQR]) cumulative urine output increased significantly and did not differ among those receiving metolazone (7.78 [IQR: 6.59 to 10.10] l) and chlorothiazide (8.77 [IQR: 7.37 to 10.86] l; p = 0.245) or tolvaptan (9.70 [IQR: 6.36 to 13.81] l; p = 0.160). Serum sodium decreased less with tolvaptan than with metolazone (+4 ± 5 vs. -1 ± 3 mEq/l; p = 0.001), but 48-h spot urine sodium was lower with tolvaptan (58 ± 25 mmol/l) than with metolazone (104 ± 16 mmol/l; p = 0.002) and with chlorothiazide (117 ± 14 mmol/l; p < 0.001).ConclusionsIn this moderately sized DR trial, weight loss was excellent with the addition of metolazone, IV chlorothiazide, or tolvaptan to loop diuretics, without a detectable between-group difference. (Comparison of Oral or Intravenous Thiazides vs. tolvaptan in Diuretic Resistant Decompensated Heart Failure [3T]; NCT02606253).
| S-EPMC7058489 | biostudies-literature
Project description:Rather than the absolute dose of diuretic or urine output, the primary signal of interest when evaluating diuretic responsiveness is the efficiency with which the kidneys can produce urine after a given dose of diuretic. As a result, we hypothesized that a metric of diuretic efficiency (DE) would capture distinct prognostic information beyond that of raw fluid output or diuretic dose.We independently analyzed 2 cohorts: (1) consecutive admissions at the University of Pennsylvania (Penn) with a primary discharge diagnosis of heart failure (n=657) and (2) patients in the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE) data set (n=390). DE was estimated as the net fluid output produced per 40 mg of furosemide equivalents, then dichotomized into high versus low DE based on the median value. There was only a moderate correlation between DE and both intravenous diuretic dose and net fluid output (r(2)?0.26 for all comparisons), indicating that DE was describing unique information. With the exception of metrics of renal function and preadmission diuretic therapy, traditional baseline characteristics, including right heart catheterization variables, were not consistently associated with DE. Low DE was associated with worsened survival even after adjusting for in-hospital diuretic dose, fluid output, in addition to baseline characteristics (Penn: hazards ratio [HR], 1.36; 95% confidence interval [CI], 1.04-1.78; P=0.02; ESCAPE: HR, 2.86; 95% CI, 1.53-5.36; P=0.001).Although in need of validation in less-selected populations, low DE during decongestive therapy portends poorer long-term outcomes above and beyond traditional prognostic factors in patients hospitalized with decompensated heart failure.
| S-EPMC4386906 | biostudies-literature
Project description:BACKGROUND:The relationship between diuretic use or change in diuretic use and outcomes in chronic heart failure (HF) remains poorly defined. We evaluated the association between diuretic use and changes in health status, exercise capacity, and clinical events in a large randomized trial of subjects with HF. METHODS:HF-ACTION randomized 2,331 outpatients with HF and ejection fraction ?35% to aerobic exercise training versus usual care. We grouped patients according to loop diuretic use from baseline through 6?months: continued use, never use, initiated, and discontinued. The association between diuretic use and changes in health status, exercise capacity, and clinical outcomes (all-cause mortality/hospitalization, cardiovascular mortality, and HF hospitalization) through 12?months was assessed using Cox proportional hazards models and generalized linear regression models, respectively. RESULTS:A total of 2,004 (86%) patients had complete data on diuretic use. There was no association between diuretic status and Kansas City Cardiomyopathy Questionnaire, 6-minute walk distance, or peak Vo2 in adjusted analyses (all P?>?.05). A dose increase was associated with decrease in 6-minute walk distance (-4.25 m, SE 1.12 m, P?<?.001) and change in Kansas City Cardiomyopathy Questionnaire overall score (-0.56 m, SE 0.24 m, P?=?.02). There were no between-group differences for all-cause death or hospitalization comparing continuous use versus never use (adjusted HR 0.91; 95% CI 0.72-1.15; P?=?.432). CONCLUSIONS:The initiation or discontinuation of diuretics over a 6-month time frame was not associated with a difference in mortality, hospitalizations, exercise, or health status outcomes, but a dose increase in HF patients was associated with worse exercise and health status outcomes.
| S-EPMC6283675 | biostudies-literature
Project description:BACKGROUND:Despite the fact that loop diuretics are a landmark in acute heart failure (AHF) treatment, few trials exist that evaluate whether the duration and timing of their administration and drug amount affect outcome. In this study, we sought to evaluate different loop diuretic infusion doses in relation to outcome and to diuretic response (DR), which was serially measured during hospitalization. METHODS:This is a post-hoc analysis of a DIUR-HF trial. We divided our sample on the basis of intravenous diuretic dose during hospitalization. Patients taking less than 125 mg of intravenous furosemide (median value) were included in the low dose group (LD), patients with a diuretic amount above this threshold were inserted in the high dose group (HD). The DR formula was defined as weight loss/40 mg daily of furosemide and it was measured during the first 24 h, 72 h, and over the whole infusion period. Outcome was considered as death due to cardiovascular causes or heart failure hospitalization. RESULTS:One hundred and twenty-one AHF patients with reduced ejection fractions (EF) were evaluated. The cardiovascular (CV) death/heart failure (HF) re-hospitalization rate was significantly higher in the HD group compared to the LD group (75% vs. 22%; p < 0.001). Both low DR, measured during the entire infusion period (HR 3.25 (CI: 1.92-5.50); p < 0.001) and the intravenous diuretic HD (HR 5.43 [CI: 2.82-10.45]; p < 0.001) were related to outcome occurrence. Multivariable analysis showed that DR (HR 3.01 (1.36-6.65); p = 0.006), intravenous diuretic HD (HR 2.83 (1.24-6.42); p=0.01) and worsening renal function (WRF) (HR 2.21 (1.14-4.28); p = 0.01) were related to poor prognosis. CONCLUSIONS:HD intravenous loop diuretic administration is associated with poor prognosis and less DR. Low DR measured during the whole intravenous administration better predicts outcome compared to DR measured in the early phases. ClinicalTrials.gov Acronym and Identifier Number: DIUR-HF; NCT01441245; registered on 23 September 2011.
| S-EPMC6912499 | biostudies-literature
Project description:BACKGROUND:Loop diuretic resistance is a common barrier to effective decongestion in acute heart failure (AHF), and is associated with poor outcome. Specific mechanisms underlying diuretic resistance are currently unknown in contemporary AHF patients. We therefore aimed to determine the relative importance of defects in diuretic delivery vs. renal tubular response in determining diuretic response (DR) in AHF. METHODS AND RESULTS:Fifty AHF patients treated with intravenous bumetanide underwent a 6-h timed urine collection for sodium and bumetanide clearance. Whole-kidney DR was defined as sodium excreted per doubling of administered loop diuretic and represents the sum of defects in drug delivery and renal tubular response. Tubular DR, defined as sodium excreted per doubling of renally cleared (urinary) loop diuretic, captures resistance specifically in the renal tubule. Median administered bumetanide dose was 3.0 (2.0-4.0) mg with 52 (33-77)% of the drug excreted into the urine. Significant between-patient variability was present as the administered dose only explained 39% of variability in the quantity of bumetanide in urine. Cumulatively, factors related to drug delivery such as renal bumetanide clearance, administered dose, and urea clearance explained 28% of the variance in whole-kidney DR. However, resistance at the level of the renal tubule (tubular DR) explained 71% of the variability in whole-kidney DR. CONCLUSION:Defects at the level of the renal tubule are substantially more important than reduced diuretic delivery in determining diuretic resistance in patients with AHF.
| S-EPMC6231236 | biostudies-literature
Project description:The purpose of this study was to investigate whether a surrogate for renal neurohormonal activation, blood urea nitrogen (BUN), could identify patients destined to experience adverse outcomes associated with the use of high-dose loop diuretics (HDLD).Loop diuretics are commonly used to control congestive symptoms in heart failure; however, these agents cause neurohormonal activation and have been associated with worsened survival.Subjects in the BEST (Beta-Blocker Evaluation of Survival Trial) receiving loop diuretics at baseline were analyzed (N = 2,456). The primary outcome was the interaction between BUN- and HDLD-associated mortality.In the overall cohort, HDLD use (?160 mg/day) was associated with increased mortality (hazard ratio [HR]: 1.56; 95% confidence interval [CI]: 1.35 to 1.80). However, after extensively controlling for baseline characteristics, this association did not persist (HR: 1.06; 95% CI: 0.89 to 1.25). In subjects with BUN levels above the median (21.0 mg/dl), both the unadjusted (HR: 1.59; 95% CI: 1.34 to 1.88) and adjusted (HR: 1.29; 95% CI: 1.07 to 1.60) risk of death was higher in the HDLD group. In patients with BUN levels below the median, there was no associated risk with HDLD (HR: 0.99; 95% CI: 0.75 to 1.34) and after controlling for baseline characteristics, the HDLD group had significantly improved survival (HR: 0.71; 95% CI: 0.49 to 0.96) (p interaction = 0.018).The risk associated with HDLD use is strongly dependent on BUN concentrations with reduced survival in patients with an elevated BUN level and improved survival in patients with a normal BUN level. These data suggest a role for neurohormonal activation in loop diuretic-associated mortality.
| S-EPMC3980479 | biostudies-literature
Project description:AimsAlthough loop diuretics are the most commonly used drugs in acute heart failure (AHF) treatment, their short-term and long-term effects are relatively unknown. The significance of worsening renal function occurrence during intravenous treatment is not clear enough. This trial aims to clarify all these features and contemplate whether continuous infusion is better than an intermittent strategy in terms of decongestion efficacy, diuretic efficiency, renal function, and long-term prognosis.Methods and resultsThis is a prospective, multicentre, randomized study that compares continuous infusion to intermittent infusion and a low vs. high diuretic dose of furosemide in patients with a diagnosis of acute heart failure, BNP ≥ 100 pg/mL, and specific chest X-ray signs. Randomization criteria have been established at a 1:1 ratio using a computer-generated scheme of either twice-daily bolus injection or continuous infusion for a time period ranging from 72 to 120 h. The initial dose will be 80 mg/day of intravenous furosemide and, in the case of poor response, will be doubled using an escalation algorithm. A high diuretic dose is defined as a furosemide daily amount >120 mg/day respectively.ConclusionsContinuous and high dose groups could reveal a more intensive diuresis and a greater decongestion with respect to intermittent and low dose groups; high dose and poor loop diuretic efficiency should be related to increased diuretic resistance, renal dysfunction occurrence, and greater congestion status. Poor diuretic response will be associated with less decongestion and an adverse prognosis.
| S-EPMC5695186 | biostudies-literature
Project description:Measurement of natriuresis has been suggested as a reliable, easily obtainable biomarker for assessment of the response to diuretic treatment in patients with acute heart failure (AHF). Here, to assess whether natriuresis-guided diuretic therapy in patients with AHF improves natriuresis and clinical outcomes, we conducted the pragmatic, open-label Pragmatic Urinary Sodium-based algoritHm in Acute Heart Failure trial, in which 310 patients (45% female) with AHF requiring treatment with intravenous loop diuretics were randomly assigned to natriuresis-guided therapy or standard of care (SOC). In the natriuresis-guided arm, natriuresis was determined at set timepoints, prompting treatment intensification if spot urinary sodium levels were <70 mmol l-1. The dual primary endpoints were 24 h urinary sodium excretion and a combined endpoint of time to all-cause mortality or adjudicated heart failure rehospitalization at 180 days. The first primary endpoint was met, as natriuresis in the natriuresis-guided and SOC arms was 409 ± 178 mmol arm versus 345 ± 202 mmol, respectively (P = 0.0061). However, there were no significant differences between the two arms for the combined endpoint of time to all-cause mortality or first heart failure rehospitalization, which occurred in 46 (31%) and 50 (31%) of patients in the natriuresis-guided and SOC arms, respectively (hazard ratio 0.92 [95% confidence interval 0.62-1.38], P = 0.6980). These findings suggest that natriuresis-guided therapy could be a first step towards personalized treatment of AHF. ClinicalTrials.gov registration: NCT04606927 .
| S-EPMC10579092 | biostudies-literature
Project description:BackgroundDiuretic Resistance in Acute Heart Failure (DR-AHF) was designed to demonstrate the effectiveness of the early tolvaptan (a vasopressin-2 receptor antagonist) add-on therapy in patients with AHF with renal dysfunction and to provide clinical evidence of loop diuretic resistance.Methods and resultsThis single-centered, open-labeled, randomized, and controlled trial enrolled 128 patients hospitalized with AHF, as participants. These patients with a wet-warm phenotype, whose estimated glomerular filtration rates are of ≥15 ml/min/1.73 m2 and ≤ 60 ml/min/1.73 m2, with a cumulative urine output of <300 ml 2 h after the first dose of intravenous furosemide, will be randomly assigned 1:1 to receive standard care with an uptitrating intravenous furosemide alone, or a combination therapy with 15 mg of tolvaptan administered once daily for 2 days. The standard furosemide treatment will follow the latest position statements of the Heart Failure Association. The primary endpoint is the cumulative urine output at 48 h. The key secondary endpoints include the improvement of fractional excretion of sodium at 6 h, the total dose of furosemide, and the incidence of worsening renal function (WRF) at 48 h.ConclusionsAlthough the combination of diuretic treatment has recently gained more attention due to its physiologically synergistic action, its advantages may be outweighed by the substantial risk of electrolyte disturbances and severe WRF. Further, there is no consensus on the time point for early starting of add-on therapy and for the preferred diuretic combination.Trial registrationNCT04331132.
| S-EPMC8829876 | biostudies-literature
Project description:Intravenous loop diuretics are a cornerstone of therapy in acutely decompensated heart failure (ADHF). We sought to determine if there are any differences in clinical outcomes between intravenous bolus and continuous infusion of loop diuretics.Subjects with ADHF within 12 hours of hospital admission were randomly assigned to continuous infusion or twice daily bolus therapy with furosemide. There were three co-primary endpoints assessed from admission to discharge: the mean paired changes in serum creatinine, estimated glomerular filtration rate (eGFR), and reduction in B-type natriuretic peptide (BNP). Secondary endpoints included the rate of acute kidney injury (AKI), change in body weight and six months follow-up evaluation after discharge.A total of 43 received a continuous infusion and 39 were assigned to bolus treatment. At discharge, the mean change in serum creatinine was higher (+0.8 ± 0.4 versus -0.8 ± 0.3 mg/dl P <0.01), and eGFR was lower (-9 ± 7 versus +5 ± 6 ml/min/1.73 m(2) P <0.05) in the continuous arm. There was no significant difference in the degree of weight loss (-4.1 ± 1.9 versus -3.5 ± 2.4 kg P = 0.23). The continuous infusion arm had a greater reduction in BNP over the hospital course, (-576 ± 655 versus -181 ± 527 pg/ml P = 0.02). The rates of AKI were comparable (22% and 15% P = 0.3) between the two groups. There was more frequent use of hypertonic saline solutions for hyponatremia (33% versus 18% P <0.01), intravenous dopamine infusions (35% versus 23% P = 0.02), and the hospital length of stay was longer in the continuous infusion group (14. 3 ± 5 versus 11.5 ± 4 days, P <0.03). At 6 months there were higher rates of re-admission or death in the continuous infusion group, 58% versus 23%, (P = 0.001) and this mode of treatment independently associated with this outcome after adjusting for baseline and intermediate variables (adjusted hazard ratio = 2.57, 95% confidence interval, 1.01 to 6.58 P = 0.04).In the setting of ADHF, continuous infusion of loop diuretics resulted in greater reductions in BNP from admission to discharge. However, this appeared to occur at the consequence of worsened renal filtration function, use of additional treatment, and higher rates of rehospitalization or death at six months.ClinicalTrials.gov NCT01441245. Registered 23 September 2011.
| S-EPMC4227080 | biostudies-literature