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ESC Heart Failure Dec 2021Although acute heart failure (AHF) with volume overload is treated with loop diuretics, their dosing and type of administration are mainly based upon expert opinion. A...
AIMS
Although acute heart failure (AHF) with volume overload is treated with loop diuretics, their dosing and type of administration are mainly based upon expert opinion. A recent position paper from the Heart Failure Association (HFA) proposed a step-wise pharmacologic diuretic strategy to increase the diuretic response and to achieve rapid decongestion. However, no study has evaluated this protocol prospectively.
METHODS AND RESULTS
The Efficacy of a Standardized Diuretic Protocol in Acute Heart Failure (ENACT-HF) study is an international, multicentre, non-randomized, open-label, pragmatic study in AHF patients on chronic loop diuretic therapy, admitted to the hospital for intravenous loop diuretic therapy, aiming to enrol 500 patients. Inclusion criteria are as follows: at least one sign of volume overload (oedema, ascites, or pleural effusion), use ≥ 40 mg of furosemide or equivalent for >1 month, and a BNP > 250 ng/L or an N-terminal pro-B-type natriuretic peptide > 1000 pg/L. The study is designed in two sequential phases. During Phase 1, all centres will treat consecutive patients according to the local standard of care. In the Phase 2 of the study, all centres will implement a standardized diuretic protocol in the next cohort of consecutive patients. The protocol is based upon the recently published HFA algorithm on diuretic use and starts with intravenous administration of two times the oral home dose. It includes early assessment of diuretic response with a spot urinary sodium measurement after 2 h and urine output after 6 h. Diuretics will be tailored further based upon these measurements. The study is powered for its primary endpoint of natriuresis after 1 day and will be able to detect a 15% difference with 80% power. Secondary endpoints are natriuresis and diuresis after 2 days, change in congestion score, change in weight, in-hospital mortality, and length of hospitalization.
CONCLUSIONS
The ENACT-HF study will investigate whether a step-wise diuretic approach, based upon early assessment of urinary sodium and urine output as proposed by the HFA, is feasible and able to improve decongestion in AHF with volume overload.
Topics: Diuretics; Furosemide; Heart Failure; Humans; Infusions, Intravenous; Sodium Potassium Chloride Symporter Inhibitors
PubMed: 34708555
DOI: 10.1002/ehf2.13666 -
European Heart Journal Aug 2023Dapagliflozin reduced the combined risk of worsening heart failure or cardiovascular death among patients with heart failure with mildly reduced or preserved ejection...
AIMS
Dapagliflozin reduced the combined risk of worsening heart failure or cardiovascular death among patients with heart failure with mildly reduced or preserved ejection fraction. In this study, the safety and efficacy of dapagliflozin according to background diuretic therapy and the influence of dapagliflozin on longitudinal diuretic use were evaluated.
METHODS AND RESULTS
In this pre-specified analysis of the Dapagliflozin Evaluation to Improve the LIVEs of Patients With Preserved Ejection Fraction Heart Failure (DELIVER) trial, the effects of dapagliflozin vs. placebo were assessed in the following subgroups: no diuretic, non-loop diuretic, and loop diuretic furosemide equivalent doses of <40, 40, and >40 mg, respectively. Of the 6263 randomized patients, 683 (10.9%) were on no diuretic, 769 (12.3%) were on a non-loop diuretic, and 4811 (76.8%) were on a loop diuretic at baseline. Treatment benefits of dapagliflozin on the primary composite outcome were consistent by diuretic use categories (Pinteraction = 0.64) or loop diuretic dose (Pinteraction = 0.57). Serious adverse events were similar between dapagliflozin and placebo arms, irrespective of diuretic use or dosing. Dapagliflozin reduced new initiation of loop diuretics by 32% [hazard ratio (HR) 0.68; 95% confidence interval (CI): 0.55-0.84, P < 0.001] but did not influence discontinuations/disruptions (HR 0.98; 95% CI: 0.86-1.13, P = 0.83) in follow-up. First sustained loop diuretic dose increases were less frequent, and sustained dose decreases were more frequent in patients treated with dapagliflozin: net difference of -6.5% (95% CI: -9.4 to -3.6; P < 0.001). The mean dose of loop diuretic increased over time in the placebo arm, a longitudinal increase that was significantly attenuated with treatment with dapagliflozin (placebo-corrected treatment effect of -2.5 mg/year; 95% CI: -1.5, -3.7, P < 0.001).
CONCLUSION
In patients with heart failure with mildly reduced or preserved ejection fraction, the clinical benefits of dapagliflozin relative to placebo were consistent across a wide range of diuretic categories and doses with a similar safety profile. Treatment with dapagliflozin significantly reduced new loop diuretic requirement over time.
Topics: Humans; Diuretics; Heart Failure; Furosemide; Benzhydryl Compounds; Sodium Potassium Chloride Symporter Inhibitors; Stroke Volume; Ventricular Function, Left
PubMed: 37220093
DOI: 10.1093/eurheartj/ehad283 -
Nature Feb 2023The sodium-chloride cotransporter (NCC) is critical for kidney physiology. The NCC has a major role in salt reabsorption in the distal convoluted tubule of the nephron,...
The sodium-chloride cotransporter (NCC) is critical for kidney physiology. The NCC has a major role in salt reabsorption in the distal convoluted tubule of the nephron, and mutations in the NCC cause the salt-wasting disease Gitelman syndrome. As a key player in salt handling, the NCC regulates blood pressure and is the target of thiazide diuretics, which have been widely prescribed as first-line medications to treat hypertension for more than 60 years. Here we determined the structures of human NCC alone and in complex with a commonly used thiazide diuretic using cryo-electron microscopy. These structures, together with functional studies, reveal major conformational states of the NCC and an intriguing regulatory mechanism. They also illuminate how thiazide diuretics specifically interact with the NCC and inhibit its transport function. Our results provide critical insights for understanding the Na-Cl cotransport mechanism of the NCC, and they establish a framework for future drug design and for interpreting disease-related mutations.
Topics: Humans; Cryoelectron Microscopy; Diuretics; Drug Design; Gitelman Syndrome; Sodium Chloride Symporter Inhibitors; Thiazides
PubMed: 36792826
DOI: 10.1038/s41586-023-05718-0 -
Current Heart Failure Reports Feb 2023Heart failure is characterized by episodes of congestion with need for hospitalization. The current metrics lack the accuracy to predict and prevent episodes of... (Review)
Review
PURPOSE OF REVIEW
Heart failure is characterized by episodes of congestion with need for hospitalization. The current metrics lack the accuracy to predict and prevent episodes of congestion and to guide diuretic titration to reach euvolemia in case of decompensation. This article aims to provide answers to the role of urinary sodium measurements in acute and chronic heart failure.
RECENT FINDINGS
In acute heart failure, urinary sodium concentrations at the moment of admission and after diuretic administration are correlated with short- and long-term outcome. As this is a reflection of the degree of sodium retention, it can be used as a guide in the diuretic titration. In chronic heart failure, it might be used to predict and consequently prevent episodes of decompensation. Urinary sodium measurements hold great promises to be a novel diagnostic and therapeutic parameter in patients with acute and chronic heart failure. However, more research is needed.
Topics: Humans; Heart Failure; Follow-Up Studies; Sodium Potassium Chloride Symporter Inhibitors; Diuretics; Sodium; Chronic Disease
PubMed: 36807114
DOI: 10.1007/s11897-023-00591-4 -
Journal of the... 2020Amiloride is a potassium retaining diuretic and natriuretic which acts by reversibly blocking luminal epithelial sodium channels (ENaCs) in the late distal tubule and... (Review)
Review
Amiloride is a potassium retaining diuretic and natriuretic which acts by reversibly blocking luminal epithelial sodium channels (ENaCs) in the late distal tubule and collecting duct. Amiloride is indicated in oedematous states, and for potassium conservation adjunctive to thiazide or loop diuretics for hypertension, congestive heart failure and hepatic cirrhosis with ascites. Historical studies on its use in hypertension were poorly controlled and there is insufficient data on dose-response. It is clearly highly effective in combination with thiazide diuretics where it counteracts the adverse metabolic effects of the thiazides and its use in the Medical Research Council Trial of Older Hypertensive Patients, demonstrated convincing outcome benefits on stroke and coronary events. Recently it has been shown to be as effective as spironolactone in resistant hypertension but there is a real need to establish its potential role in the much larger number of patients with mild to moderate hypertension in whom there is a paucity of information with amiloride particularly across an extended dose range.
Topics: Amiloride; Animals; Clinical Trials as Topic; Diuretics; Humans; Hypertension
PubMed: 33234024
DOI: 10.1177/1470320320975893 -
Journal of the American College of... Apr 2024The primary goals during acute heart failure (AHF) hospitalization are decongestion and guideline-directed medical therapy (GDMT) optimization. Unlike diuretics or other... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
The primary goals during acute heart failure (AHF) hospitalization are decongestion and guideline-directed medical therapy (GDMT) optimization. Unlike diuretics or other GDMT, early dapagliflozin initiation could achieve both AHF goals.
OBJECTIVES
The authors aimed to assess the diuretic efficacy and safety of early dapagliflozin initiation in AHF.
METHODS
In a multicenter, open-label study, 240 patients were randomized within 24 hours of hospital presentation for hypervolemic AHF to dapagliflozin 10 mg once daily or structured usual care with protocolized diuretic titration until day 5 or hospital discharge. The primary outcome, diuretic efficiency expressed as cumulative weight change per cumulative loop diuretic dose, was compared across treatment assignment using a proportional odds model adjusted for baseline weight. Secondary and safety outcomes were adjudicated by a blinded committee.
RESULTS
For diuretic efficiency, there was no difference between dapagliflozin and usual care (OR: 0.65; 95% CI: 0.41-1.02; P = 0.06). Dapagliflozin was associated with reduced loop diuretic doses (560 mg [Q1-Q3: 260-1,150 mg] vs 800 mg [Q1-Q3: 380-1,715 mg]; P = 0.006) and fewer intravenous diuretic up-titrations (P ≤ 0.05) to achieve equivalent weight loss as usual care. Early dapagliflozin initiation did not increase diabetic, renal, or cardiovascular safety events. Dapagliflozin was associated with improved median 24-hour natriuresis (P = 0.03) and urine output (P = 0.005), expediting hospital discharge over the study period.
CONCLUSIONS
Early dapagliflozin during AHF hospitalization is safe and fulfills a component of GDMT optimization. Dapagliflozin was not associated with a statistically significant reduction in weight-based diuretic efficiency but was associated with evidence for enhanced diuresis among patients with AHF. (Efficacy and Safety of Dapagliflozin in Acute Heart Failure [DICTATE-AHF]; NCT04298229).
Topics: Humans; Sodium Potassium Chloride Symporter Inhibitors; Acute Disease; Heart Failure; Diuretics; Benzhydryl Compounds; Glucosides
PubMed: 38569758
DOI: 10.1016/j.jacc.2024.02.009 -
Anaesthesia Feb 2018Loop diuretics remain a fundamental pharmacological therapy to remove excess fluid and improve symptom control in acute decompensated heart failure. Several recent... (Comparative Study)
Comparative Study Meta-Analysis
Continuous infusion vs. intermittent bolus injection of furosemide in acute decompensated heart failure: systematic review and meta-analysis of randomised controlled trials.
Loop diuretics remain a fundamental pharmacological therapy to remove excess fluid and improve symptom control in acute decompensated heart failure. Several recent randomised controlled trials have examined the clinical benefit of continuous vs. bolus furosemide in acute decompensated heart failure, but have reported conflicting findings. The aim of this review was to compare the effects of continuous and bolus furosemide with regard to mortality, length of hospital stay and its efficacy profile in acute decompensated heart failure. All parallel-arm randomised controlled trials from MEDLINE, EMBASE, PubMed and the Cochrane Database of Systematic Reviews from inception until May 2017 were included. Cross-over randomised controlled trials, observational studies, case reports, case series and non-systematic reviews that involved children were excluded. Eight trials (n = 669) were eligible for inclusion. There was no difference between furosemide continuous infusion and bolus administration for all-cause mortality (four studies; n = 491; I = 0%; OR 1.65; 95%CI 0.93-2.91; p = 0.08) or duration of hospitalisation (six studies; n = 576; I = 71%; mean difference 0.27; 95%CI -1.35 to 1.89 days; p = 0.74). Continuous infusion of intravenous furosemide was associated with increased weight reduction (five studies; n = 516; I = 0%; mean difference 0.70; 95%CI 0.12-1.28 kg; p = 0.02); increased total urine output in 24 h (four studies; n = 390; I = 33%; mean difference 461.5; 95%CI 133.7-789.4 ml; p < 0.01); and reduced brain natriuretic peptide (two studies; n = 390; I = 0%; mean difference 399.5; 95%CI 152.7-646.3 ng.l ; p < 0.01), compared with the bolus group. There was no difference in the incidence of raised creatinine and hypokalaemia between the two groups. In summary, there was no difference between continuous infusion and bolus of furosemide for all-cause mortality, length of hospital stay and electrolyte disturbance, but continuous infusion was superior to bolus administration with regard to diuretic effect and reduction in brain natriuretic peptide.
Topics: Acute Disease; Diuretics; Furosemide; Heart Failure; Humans; Infusions, Intravenous; Injections, Intravenous; Length of Stay
PubMed: 28940440
DOI: 10.1111/anae.14038 -
Clinical Journal of the American... Oct 2023In contrast to significant advances in the management of patients with chronic heart failure over the past few years, there has been little change in how patients with... (Review)
Review
In contrast to significant advances in the management of patients with chronic heart failure over the past few years, there has been little change in how patients with acute heart failure are treated. Symptoms and signs of fluid overload are the primary reason for hospitalization of patients who experience acute decompensation of heart failure. Intravenous loop diuretics remain the mainstay of therapy in this patient population, with a significant subset of them showing suboptimal response to these agents leading to incomplete decongestion at the time of discharge. Combination diuretic therapy, that is, using loop diuretics along with an add-on agent, is a widely applied strategy to counter renal sodium avidity through sequential blockade of sodium absorption within renal tubules. The choice of the second diuretic is affected by several factors, including the site of action, the anticipated secondary effects, and the available evidence on their efficacy and safety. While the current guidelines recommend combination diuretic therapy as a viable option to overcome suboptimal response to loop diuretics, it is also acknowledged that this strategy is not supported by strong evidence and remains an area of uncertainty. The recent publication of landmark studies has regenerated the interest in sequential nephron blockade. In this article, we provide an overview of the results of the key studies on combination diuretic therapy in the setting of acute heart failure and discuss their findings primarily with regard to the effect on renal sodium avidity and cardiorenal outcomes.
Topics: Humans; Diuretics; Heart Failure; Kidney; Sodium; Sodium Potassium Chloride Symporter Inhibitors
PubMed: 37102974
DOI: 10.2215/CJN.0000000000000188 -
Nature Medicine Oct 2023Measurement of natriuresis has been suggested as a reliable, easily obtainable biomarker for assessment of the response to diuretic treatment in patients with acute... (Randomized Controlled Trial)
Randomized Controlled Trial
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. 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 .
Topics: Female; Humans; Male; Acute Disease; Diuretics; Heart Failure; Natriuresis; Sodium; Sodium Potassium Chloride Symporter Inhibitors
PubMed: 37640861
DOI: 10.1038/s41591-023-02532-z -
JAMA Network Open Dec 2023The long-term relative risk of antihypertensive treatments with regard to mortality and morbidity is not well understood. (Randomized Controlled Trial)
Randomized Controlled Trial
Mortality and Morbidity Among Individuals With Hypertension Receiving a Diuretic, ACE Inhibitor, or Calcium Channel Blocker: A Secondary Analysis of a Randomized Clinical Trial.
IMPORTANCE
The long-term relative risk of antihypertensive treatments with regard to mortality and morbidity is not well understood.
OBJECTIVE
To determine the long-term posttrial risk of primary and secondary outcomes among trial participants who were randomized to either a thiazide-type diuretic, calcium channel blocker (CCB), or angiotensin-converting enzyme (ACE) inhibitor with up to 23 years of follow-up.
DESIGN, SETTING, AND PARTICIPANTS
This prespecified secondary analysis of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), a multicenter randomized, double-blind, active-controlled clinical trial, followed up with participants aged 55 years or older with a diagnosis of hypertension and at least 1 other coronary heart disease risk factor for up to 23 years, from February 23, 1994, to December 31, 2017. Trial participants were linked with administrative databases for posttrial mortality (N = 32 804) and morbidity outcomes (n = 22 754). Statistical analysis was performed from January 2022 to October 2023.
INTERVENTIONS
Participants were randomly assigned to receive a thiazide-type diuretic (n = 15 002), a CCB (n = 8898), or an ACE inhibitor (n = 8904) for planned in-trial follow-up of approximately 4 to 8 years and posttrial passive follow-up for up to 23 years.
MAIN OUTCOMES AND MEASURES
The primary end point was mortality due to cardiovascular disease (CVD). Secondary outcomes included all-cause mortality, combined fatal and nonfatal (morbidity) CVD, and both mortality and morbidity for coronary heart disease, stroke, heart failure, end-stage renal disease, and cancer.
RESULTS
A total of 32 804 participants (mean [SD] age, 66.9 [7.7] years; 17 411 men [53.1%]; and 11 772 Black participants [35.9%]) were followed up for all-cause mortality and a subgroup of 22 754 participants (mean [SD] age, 68.7 [7.2] years; 12 772 women [56.1%]; and 8199 Black participants [36.0%]) were followed up for fatal or nonfatal CVD through 2017 (mean [SD] follow-up, 13.7 [6.7] years; maximum follow-up, 23.9 years). Cardiovascular disease mortality rates per 100 persons were 23.7, 21.6, and 23.8 in the diuretic, CCB, and ACE inhibitor groups, respectively, at 23 years after randomization (adjusted hazard ratio [AHR], 0.97 [95% CI, 0.89-1.05] for CCB vs diuretic; AHR, 1.06 [95% CI, 0.97-1.15] for ACE inhibitor vs diuretic). The long-term risks of most secondary outcomes were similar among the 3 groups. Compared with the diuretic group, the ACE inhibitor group had a 19% increased risk of stroke mortality (AHR, 1.19 [95% CI, 1.03-1.37]) and an 11% increased risk of combined fatal and nonfatal hospitalized stroke (AHR, 1.11 [95% CI, 1.03-1.20]).
CONCLUSIONS AND RELEVANCE
In this secondary analysis of a randomized clinical trial in an adult population with hypertension and coronary heart disease risk factors, CVD mortality was similar between all 3 groups. ACE inhibitors increased the risk of stroke outcomes by 11% compared with diuretics, and this effect persisted well beyond the trial period.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT00000542.
Topics: Adult; Male; Female; Humans; Aged; Angiotensin-Converting Enzyme Inhibitors; Diuretics; Antihypertensive Agents; Calcium Channel Blockers; Cardiovascular Diseases; Hypertension; Thiazides; Sodium Chloride Symporter Inhibitors; Stroke; Antiviral Agents; Coronary Disease
PubMed: 38048133
DOI: 10.1001/jamanetworkopen.2023.44998