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European Journal of Heart Failure Feb 2019The vast majority of acute heart failure episodes are characterized by increasing symptoms and signs of congestion with volume overload. The goal of therapy in those... (Review)
Review
The vast majority of acute heart failure episodes are characterized by increasing symptoms and signs of congestion with volume overload. The goal of therapy in those patients is the relief of congestion through achieving a state of euvolaemia, mainly through the use of diuretic therapy. The appropriate use of diuretics however remains challenging, especially when worsening renal function, diuretic resistance and electrolyte disturbances occur. This position paper focuses on the use of diuretics in heart failure with congestion. The manuscript addresses frequently encountered challenges, such as (i) evaluation of congestion and clinical euvolaemia, (ii) assessment of diuretic response/resistance in the treatment of acute heart failure, (iii) an approach towards stepped pharmacologic diuretic strategies, based upon diuretic response, and (iv) management of common electrolyte disturbances. Recommendations are made in line with available guidelines, evidence and expert opinion.
Topics: Cardiology; Consensus; Diuretics; Europe; Heart Failure; Humans; Societies, Medical; Stroke Volume
PubMed: 30600580
DOI: 10.1002/ejhf.1369 -
Journal of the American College of... Mar 2020Expansion of extracellular fluid volume is central to the pathophysiology of heart failure. Increased extracellular fluid leads to elevated intracardiac filling... (Review)
Review
Expansion of extracellular fluid volume is central to the pathophysiology of heart failure. Increased extracellular fluid leads to elevated intracardiac filling pressures, resulting in a constellation of signs and symptoms of heart failure referred to as congestion. Loop diuretics are one of the cornerstones of treatments for heart failure, but in contrast to other therapies, robust clinical trial evidence to guide the use of diuretics is sparse. A nuanced understanding of renal physiology and diuretic pharmacokinetics is essential for skillful use of diuretics in the management of heart failure in both the inpatient and outpatient settings. Diuretic resistance, defined as an inadequate quantity of natriuresis despite an adequate diuretic regimen, is a major clinical challenge that generally portends a poor prognosis. In this review, the authors discuss the fundamental mechanisms and physiological principles that underlie the use of diuretic therapy and the available data on the optimal use of diuretics.
Topics: Diuretics; Gastrointestinal Absorption; Heart Failure; Humans; Kidney; Review Literature as Topic; Sodium Potassium Chloride Symporter Inhibitors
PubMed: 32164892
DOI: 10.1016/j.jacc.2019.12.059 -
Current Heart Failure Reports Apr 2019Diuretic resistance (DR) occurs along a spectrum of relative severity and contributes to worsening of acute heart failure (AHF) during an inpatient stay. This review... (Review)
Review
PURPOSE OF REVIEW
Diuretic resistance (DR) occurs along a spectrum of relative severity and contributes to worsening of acute heart failure (AHF) during an inpatient stay. This review gives an overview of mechanisms of DR with a focus on loop diuretics and summarizes the current literature regarding the prognostic value of diuretic efficiency and predictors of natriuretic response in AHF.
RECENT FINDINGS
The pharmacokinetics of diuretics are impaired in chronic heart failure, but little is known about mechanisms of DR in AHF. Almost all diuresis after administration of a loop diuretic dose occurs in the first few hours after administration and within-dose DR can develop. Recent studies suggest that DR at the level of the nephron may be more important than defects in diuretic delivery to the tubule. Because loop diuretics induce natriuresis, urine sodium (UNa) concentration may serve as a functional, physiological, and direct measure for diuretic responsiveness to a given loop diuretic dose. Identifying and targeting individuals with DR for more aggressive, tailored therapy represents an important opportunity to improve outcomes. A better understanding of the mechanistic underpinnings of DR in AHF is needed to identify additional biomarkers and guide future trials and therapies.
Topics: Diuretics; Drug Resistance; Heart Failure; Humans; Nephrons; Prognosis; Sodium; Sodium Potassium Chloride Symporter Inhibitors
PubMed: 30762178
DOI: 10.1007/s11897-019-0424-1 -
Journal of the American College of... Jan 2023Heart failure (HF) is a progressive disease characterized by variable durations of symptomatic stability often punctuated by episodes of worsening despite continued... (Review)
Review
Heart failure (HF) is a progressive disease characterized by variable durations of symptomatic stability often punctuated by episodes of worsening despite continued therapy. These periods of clinical worsening are increasingly recognized as a distinct phase in the history of HF, termed worsening HF (WHF). The definition of WHF continues to evolve from a historical focus solely on hospitalization to now include nonhospitalization events (eg, need for intravenous diuretic therapy in the emergency or outpatient setting). Most HF clinical trials to date have had HF hospitalization and death as primary endpoints, and only recently, some studies have included other WHF events regardless of location of care. This article reviews the evolution of the WHF definition, highlights the importance of considering the onset of WHF as an event that marks a new phase of HF, summarizes the latest clinical trials investigating novel therapies, and outlines unmet needs regarding identification and treatment of WHF.
Topics: Humans; Acute Disease; Disease Progression; Diuretics; Heart Failure; Hospitalization
PubMed: 36697141
DOI: 10.1016/j.jacc.2022.11.023 -
Naunyn-Schmiedeberg's Archives of... Jun 2022Diuretics are drugs that increase the flow of urine. They are commonly used to treat edema, hypertension, and heart failure. Typically, the pharmacological group... (Review)
Review
Diuretics are drugs that increase the flow of urine. They are commonly used to treat edema, hypertension, and heart failure. Typically, the pharmacological group consists of five classes: thiazide diuretics, loop diuretics, potassium-sparing diuretics, osmotic diuretics, and carbonic anhydrase inhibitors. This traditional classification and the nomenclature of diuretics have not changed over the last decades, which means that it was not adapted to current pharmacological research. Modern approaches in the field of pharmacological nomenclature suggest the introduction of mechanism-based drug class designations, which is not yet reflected in the group of diuretics. Moreover, included drug classes have lost their relevance as diuretic agents. Carbonic anhydrase inhibitors, for example, are mainly used in the treatment of glaucoma. Newer agents such as vasopressin-2 receptor antagonists or SGLT2 inhibitors possess diuretic properties but are not included in the pharmacological group. This review discusses the currentness of the pharmacological classification of diuretics. We elaborate changes in the field of nomenclature, the contemporary medical use of classical diuretics, and new diuretic agents.
Topics: Carbonic Anhydrase Inhibitors; Diuretics; Heart Failure; Humans; Hypertension; Sodium Chloride Symporter Inhibitors
PubMed: 35294605
DOI: 10.1007/s00210-022-02228-0 -
The New England Journal of Medicine Mar 2023Nephrolithiasis is one of the most common conditions affecting the kidney and is characterized by a high risk of recurrence. Thiazide diuretic agents are widely used for... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Nephrolithiasis is one of the most common conditions affecting the kidney and is characterized by a high risk of recurrence. Thiazide diuretic agents are widely used for prevention of the recurrence of kidney stones, but data regarding the efficacy of such agents as compared with placebo are limited. Furthermore, dose-response data are also limited.
METHODS
In this double-blind trial, we randomly assigned patients with recurrent calcium-containing kidney stones to receive hydrochlorothiazide at a dose of 12.5 mg, 25 mg, or 50 mg once daily or placebo once daily. The main objective was to investigate the dose-response effect for the primary end point, a composite of symptomatic or radiologic recurrence of kidney stones. Radiologic recurrence was defined as the appearance of new stones on imaging or the enlargement of preexisting stones that had been observed on the baseline image. Safety was also assessed.
RESULTS
In all, 416 patients underwent randomization and were followed for a median of 2.9 years. A primary end-point event occurred in 60 of 102 patients (59%) in the placebo group, in 62 of 105 patients (59%) in the 12.5-mg hydrochlorothiazide group (rate ratio vs. placebo, 1.33; 95% confidence interval [CI], 0.92 to 1.93), in 61 of 108 patients (56%) in the 25-mg group (rate ratio, 1.24; 95% CI, 0.86 to 1.79), and in 49 of 101 patients (49%) in the 50-mg group (rate ratio, 0.92; 95% CI, 0.63 to 1.36). There was no relation between the hydrochlorothiazide dose and the occurrence of a primary end-point event (P = 0.66). Hypokalemia, gout, new-onset diabetes mellitus, skin allergy, and a plasma creatinine level exceeding 150% of the baseline level were more common among patients who received hydrochlorothiazide than among those who received placebo.
CONCLUSIONS
Among patients with recurrent kidney stones, the incidence of recurrence did not appear to differ substantially among patients receiving hydrochlorothiazide once daily at a dose of 12.5 mg, 25 mg, or 50 mg or placebo once daily. (Funded by the Swiss National Science Foundation and Inselspital; NOSTONE ClinicalTrials.gov number, NCT03057431.).
Topics: Humans; Hydrochlorothiazide; Kidney; Kidney Calculi; Sodium Chloride Symporter Inhibitors; Recurrence; Double-Blind Method; Dose-Response Relationship, Drug; Diuretics
PubMed: 36856614
DOI: 10.1056/NEJMoa2209275 -
Clinical Journal of the American... Aug 2019
Review
Topics: Diuretics; Edema; Extracellular Fluid; Gastrointestinal Absorption; Humans
PubMed: 30936153
DOI: 10.2215/CJN.09630818 -
Hypertension (Dallas, Tex. : 1979) Oct 2020Diuretic resistance implies a failure to increase fluid and sodium (Na) output sufficiently to relieve volume overload, edema, or congestion, despite escalating doses of... (Review)
Review
Diuretic resistance implies a failure to increase fluid and sodium (Na) output sufficiently to relieve volume overload, edema, or congestion, despite escalating doses of a loop diuretic to a ceiling level (80 mg of furosemide once or twice daily or greater in those with reduced glomerular filtration rate or heart failure). It is a major cause of recurrent hospitalizations in patients with chronic heart failure and predicts death but is difficult to diagnose unequivocally. Pharmacokinetic mechanisms include the low and variable bioavailability of furosemide and the short duration of all loop diuretics that provides time for the kidneys to restore diuretic-induced Na losses between doses. Pathophysiological mechanisms of diuretic resistance include an inappropriately high daily salt intake that exceeds the acute diuretic-induced salt loss, hyponatremia or hypokalemic, hypochloremic metabolic alkalosis, and reflex activation of the renal nerves. Nephron mechanisms include tubular tolerance that can develop even during the time that the renal tubules are exposed to a single dose of diuretic, or enhanced reabsorption in the proximal tubule that limits delivery to the loop, or an adaptive increase in reabsorption in the downstream distal tubule and collecting ducts that offsets ongoing blockade of Na reabsorption in the loop of Henle. These provide rationales for novel strategies including the concurrent use of diuretics that block these nephron segments and even sequential nephron blockade with multiple diuretics and aquaretics combined in severely diuretic-resistant patients with heart failure.
Topics: Diuretics; Drug Resistance; Heart Failure; Humans; Kidney Tubules; Treatment Failure
PubMed: 32829662
DOI: 10.1161/HYPERTENSIONAHA.120.15205 -
European Heart Journal Aug 2023To examine the decongestive effect of the sodium-glucose cotransporter 2 inhibitor dapagliflozin compared to the thiazide-like diuretic metolazone in patients... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND AND AIMS
To examine the decongestive effect of the sodium-glucose cotransporter 2 inhibitor dapagliflozin compared to the thiazide-like diuretic metolazone in patients hospitalized for heart failure and resistant to treatment with intravenous furosemide.
METHODS AND RESULTS
A multi-centre, open-label, randomized, and active-comparator trial. Patients were randomized to dapagliflozin 10 mg once daily or metolazone 5-10 mg once daily for a 3-day treatment period, with follow-up for primary and secondary endpoints until day 5 (96 h). The primary endpoint was a diuretic effect, assessed by change in weight (kg). Secondary endpoints included a change in pulmonary congestion (lung ultrasound), loop diuretic efficiency (weight change per 40 mg of furosemide), and a volume assessment score. 61 patients were randomized. The mean (±standard deviation) cumulative dose of furosemide at 96 h was 977 (±492) mg in the dapagliflozin group and 704 (±428) mg in patients assigned to metolazone. The mean (±standard deviation) decrease in weight at 96 h was 3.0 (2.5) kg with dapagliflozin compared to 3.6 (2.0) kg with metolazone [mean difference 0.65, 95% confidence interval (CI) -0.12,1.41 kg; P = 0.11]. Loop diuretic efficiency was less with dapagliflozin than with metolazone [mean 0.15 (0.12) vs. 0.25 (0.19); difference -0.08, 95% CI -0.17,0.01 kg; P = 0.10]. Changes in pulmonary congestion and volume assessment score were similar between treatments. Decreases in plasma sodium and potassium and increases in urea and creatinine were smaller with dapagliflozin than with metolazone. Serious adverse events were similar between treatments.
CONCLUSION
In patients with heart failure and loop diuretic resistance, dapagliflozin was not more effective at relieving congestion than metolazone. Patients assigned to dapagliflozin received a larger cumulative dose of furosemide but experienced less biochemical upset than those assigned to metolazone.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT04860011.
Topics: Humans; Metolazone; Sodium Potassium Chloride Symporter Inhibitors; Furosemide; Heart Failure; Diuretics; Sodium
PubMed: 37210742
DOI: 10.1093/eurheartj/ehad341 -
JAMA Cardiology Jul 2023The diuretic effect of sodium-glucose cotransporter 2 inhibitors may result in interaction with background diuretic therapy in patients with heart failure and preserved...
IMPORTANCE
The diuretic effect of sodium-glucose cotransporter 2 inhibitors may result in interaction with background diuretic therapy in patients with heart failure and preserved ejection fraction (HFpEF).
OBJECTIVE
To assess the safety and efficacy of empagliflozin in combination with background diuretic therapy and the association of empagliflozin with the need for conventional diuretics.
DESIGN, SETTING, AND PARTICIPANTS
This was a post hoc analysis of the Empagliflozin Outcome Trial in Patients with Chronic Heart Failure with Preserved Ejection Fraction (EMPEROR-Preserved). EMPEROR-Preserved was a phase 3, randomized, placebo-controlled, double-blind clinical trial conducted from March 2017 to April 2021. Patients with class II to IV heart failure and left ventricular ejection fraction greater than 40% were included. Of 5988 patients enrolled, 5815 (97.1%) had baseline data on diuretic use and were included in this analysis, which was conducted from November 2021 to August 2022.
INTERVENTIONS
Participants in EMPEROR-Preserved were randomized to empagliflozin or placebo. In this analysis, participants were divided into 4 subgroups: no diuretics and furosemide-equivalent diuretic dose of less than 40 mg, 40 mg, and greater than 40 mg at baseline.
MAIN OUTCOMES AND MEASURES
The main outcomes of interest were first hospitalization for heart failure (HHF) or cardiovascular death (CV death) and its components. Association of empagliflozin vs placebo with outcomes by baseline diuretic status (no diuretic vs any dose) and dose (no diuretic, <40 mg, 40 mg, and > 40mg) was assessed. Association of empagliflozin use with changes in diuretic therapy was also studied.
RESULTS
Among 5815 patients (mean [SD] age, 71.9 [9.4] years; 2594 [44.6%] female) with known baseline diuretic use, 1179 (20.3%) were not taking diuretics, 1725 (29.7%) were taking less than 40 mg, 1772 (30.5%) were taking 40 mg, and 1139 (19.6%) were taking greater than 40 mg. In the placebo arm, patients with higher diuretic doses had worse outcomes. Empagliflozin decreased the risk of HHF or CV death, regardless of background diuretic status (hazard ratio [HR], 0.81; 95% CI, 0.70-0.93] for the diuretic group vs HR, 0.72; 95% CI, 0.48-1.06 for the nondiuretic group; P for interaction = .58). Similarly, diuretic status was not associated with changes in improvements in first HHF, total HHF, rate of decline in estimated glomerular filtration rate, and Kansas City Cardiomyopathy Questionnaire 23 clinical summary score with empagliflozin. Findings were consistent when patients were categorized by diuretic dose. Empagliflozin was associated with a decreased likelihood of diuretic dose escalation (HR, 0.74; 95% CI, 0.65-0.84) and an increased likelihood of de-escalation (HR, 1.15; 95% CI, 1.02-1.30). Empagliflozin was associated with an increased risk of volume depletion in patients taking diuretics (HR, 1.34; 95% CI, 1.13-1.59).
CONCLUSION
In this study, treatment with empagliflozin was similar regardless of diuretic use or dose. Empagliflozin use was associated with decreased conventional diuretic dosing.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT03057951.
Topics: Humans; Female; Aged; Male; Heart Failure; Stroke Volume; Diuretics; Double-Blind Method; Ventricular Function, Left; Kidney; Glucose; Sodium
PubMed: 37223933
DOI: 10.1001/jamacardio.2023.1090