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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 -
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 -
PloS One 2021It has been a matter of much debate whether the co-administration of furosemide and albumin can achieve better diuresis and natriuresis than furosemide treatment alone.... (Comparative Study)
Comparative Study Meta-Analysis
BACKGROUND
It has been a matter of much debate whether the co-administration of furosemide and albumin can achieve better diuresis and natriuresis than furosemide treatment alone. There is inconsistency in published trials regarding the effect of this combination therapy. We, therefore, conducted this meta-analysis to explore the efficacy of furosemide and albumin co-administration and the factors potentially influencing the diuretic effect of such co-administration.
METHODS
In accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we searched the PubMed, Embase, Medline, and Cochrane databases. Prospective studies with adult populations which comparing the effect of furosemide and albumin co-administration with furosemide alone were included. The outcomes including diuretic effect and natriuresis effect measured by hourly urine output and hourly urine sodium excretion from both groups were extracted. Random effect model was applied for conducting meta-analysis. Subgroup analysis and sensitivity analysis were performed to explore potential sources of heterogeneity of treatment effects.
RESULTS
By including 13 studies with 422 participants, the meta-analysis revealed that furosemide with albumin co-administration increased urine output by 31.45 ml/hour and increased urine excretion by 1.76 mEq/hour in comparison to furosemide treatment alone. The diuretic effect of albumin and furosemide co-administration was better in participants with low baseline serum albumin levels (< 2.5 g/dL) and high prescribed albumin infusion doses (> 30 g), and the effect was more significant within 12 hours after administration. Diuretic effect of co-administration was better in those with baseline Cr > 1.2 mg/dL and natriuresis effect of co-administration was better in those with baseline eGFR < 60 ml/min/1.73m2.
CONCLUSION
Co-administration of furosemide with albumin might enhance diuresis and natriuresis effects than furosemide treatment alone but with high heterogeneity in treatment response. According to the present meta-analysis, combination therapy might provide advantages compared to the furosemide therapy alone in patients with baseline albumin levels lower than 2.5 g/dL or in patients receiving higher albumin infusion doses or in patients with impaired renal function. Owing to high heterogeneity and limited enrolled participants, further parallel randomized controlled trials are warranted to examine our outcome.
REGISTRATION
PROSEPRO ID: CRD42020211002; https://clinicaltrials.gov/.
Topics: Albumins; Diuretics; Drug Combinations; Furosemide; Humans; Nephrotic Syndrome; Randomized Controlled Trials as Topic
PubMed: 34851962
DOI: 10.1371/journal.pone.0260312 -
The New England Journal of Medicine Dec 2021Little evidence has been available to support the use of thiazide diuretics to treat hypertension in patients with advanced chronic kidney disease. (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Little evidence has been available to support the use of thiazide diuretics to treat hypertension in patients with advanced chronic kidney disease.
METHODS
We randomly assigned patients with stage 4 chronic kidney disease and poorly controlled hypertension, as confirmed by 24-hour ambulatory blood-pressure monitoring, in a 1:1 ratio to receive chlorthalidone at an initial dose of 12.5 mg per day, with increases every 4 weeks if needed to a maximum dose of 50 mg per day, or placebo; randomization was stratified according to previous use of loop diuretics. The primary outcome was the change in 24-hour ambulatory systolic blood pressure from baseline to 12 weeks. Secondary outcomes were the change from baseline to 12 weeks in the urinary albumin-to-creatinine ratio, N-terminal pro-B-type natriuretic peptide level, plasma renin and aldosterone levels, and total body volume. Safety was also assessed.
RESULTS
A total of 160 patients underwent randomization, of whom 121 (76%) had diabetes mellitus and 96 (60%) were receiving loop diuretics. At baseline, the mean (±SD) estimated glomerular filtration rate was 23.2±4.2 ml per minute per 1.73 m of body-surface area and the mean number of antihypertensive medications prescribed was 3.4±1.4. At randomization, the mean 24-hour ambulatory systolic blood pressure was 142.6±8.1 mm Hg in the chlorthalidone group and 140.1±8.1 mm Hg in the placebo group and the mean 24-hour ambulatory diastolic blood pressure was 74.6±10.1 mm Hg and 72.8±9.3 mm Hg, respectively. The adjusted change in 24-hour systolic blood pressure from baseline to 12 weeks was -11.0 mm Hg (95% confidence interval [CI], -13.9 to -8.1) in the chlorthalidone group and -0.5 mm Hg (95% CI, -3.5 to 2.5) in the placebo group. The between-group difference was -10.5 mm Hg (95% CI, -14.6 to -6.4) (P<0.001). The percent change in the urinary albumin-to-creatinine ratio from baseline to 12 weeks was lower in the chlorthalidone group than in the placebo group by 50 percentage points (95% CI, 37 to 60). Hypokalemia, reversible increases in serum creatinine level, hyperglycemia, dizziness, and hyperuricemia occurred more frequently in the chlorthalidone group than in the placebo group.
CONCLUSIONS
Among patients with advanced chronic kidney disease and poorly controlled hypertension, chlorthalidone therapy improved blood-pressure control at 12 weeks as compared with placebo. (Funded by the National Heart, Lung, and Blood Institute and the Indiana Institute of Medical Research; CLICK ClinicalTrials.gov number, NCT02841280.).
Topics: Aged; Albuminuria; Blood Pressure; Chlorthalidone; Creatinine; Diuretics; Double-Blind Method; Female; Glomerular Filtration Rate; Humans; Hypertension; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Renal Insufficiency, Chronic; Severity of Illness Index; Sodium Chloride Symporter Inhibitors
PubMed: 34739197
DOI: 10.1056/NEJMoa2110730 -
ESC Heart Failure Jun 2022Heart failure (HF) is a major cause of mortality, hospitalizations, and reduced quality of life and a major burden for the healthcare system. The number of patients that... (Review)
Review
Heart failure (HF) is a major cause of mortality, hospitalizations, and reduced quality of life and a major burden for the healthcare system. The number of patients that progress to an advanced stage of HF is growing. Only a limited proportion of these patients can undergo heart transplantation or mechanical circulatory support. The purpose of this review is to summarize medical management of patients with advanced HF. First, evidence-based oral treatment must be implemented although it is often not tolerated. New therapeutic options may soon become possible for these patients. The second goal is to lessen the symptomatic burden through both decongestion and haemodynamic improvement. Some new treatments acting on cardiac function may fulfil both these needs. Inotropic agents acting through an increase in intracellular calcium have often increased risk of death. However, in the recent Global Approach to Lowering Adverse Cardiac Outcomes Through Improving Contractility in Heart Failure (GALACTIC-HF) trial, omecamtiv mecarbil was safe and effective in the reduction of the primary outcome of cardiovascular death or HF event compared with placebo (hazard ratio, 0.92; 95% confidence interval, 0.86-0.99; P = 0.03) and its effects were larger in those patients with more severe left ventricular dysfunction. Patients with severe HF who received omecamtiv mecarbil experienced a significant treatment benefit, whereas patients without severe HF did not (P = 0.005 for interaction). Lastly, clinicians should take care of the end of life with an appropriate multidisciplinary approach. Medical treatment of advanced HF therefore remains a major challenge and a wide open area for further research.
Topics: Diuretics; Heart Failure; Humans; Palliative Care; Quality of Life; Stroke Volume
PubMed: 35352499
DOI: 10.1002/ehf2.13859 -
European Journal of Heart Failure May 2022Management of worsening heart failure (WHF) has traditionally been hospital-based, but with the rising burden of heart failure (HF), the pressure on healthcare systems... (Review)
Review
Management of worsening heart failure (WHF) has traditionally been hospital-based, but with the rising burden of heart failure (HF), the pressure on healthcare systems exerted by this disease necessitates a different strategy than long (and costly) hospital stays. A strategy for outpatient intravenous (IV) diuretic treatment of WHF has been developed in certain American centres in the past 10 years, whereas European centres have been mostly favouring 'classic' in-hospital management of WHF. Embracing novel, outpatient approaches for treating WHF could substantially reduce the burden on healthcare systems while improving patient's satisfaction and quality of life. The present article is intended to provide essential knowledge and practical guidelines aimed at helping clinicians implement these new ambulatory approaches using day hospital and/or at-home hospitalization. The topics addressed by our group of HF experts include the pathophysiological background of diuretic therapy, the most suitable profile of WHF that may be managed in an ambulatory setting, the pharmacological protocols that can be used, as well as a detailed description of healthcare structures that can be proposed to deliver these ambulatory care interventions. The practical aspects of day hospital and hospital-at-home IV diuretic administration are specifically emphasized. The algorithm provided along with the practical IV diuretic protocols should assist HF clinicians in implementing this new approach in their local clinical setting.
Topics: Chronic Disease; Diuretics; Heart Failure; Hospitalization; Humans; Outpatients; Quality of Life
PubMed: 35417093
DOI: 10.1002/ejhf.2503 -
Clinical Research in Cardiology :... Aug 2023We sought to compare cardiovascular outcomes, renal function, and diuresis in patients receiving standard diuretic therapy for acute heart failure (AHF) with or without... (Comparative Study)
Comparative Study Meta-Analysis
BACKGROUND
We sought to compare cardiovascular outcomes, renal function, and diuresis in patients receiving standard diuretic therapy for acute heart failure (AHF) with or without the addition of SGLT2i.
METHODS AND RESULTS
Systematic search of three electronic databases identified nine eligible randomized controlled trials involving 2,824 patients. The addition of SGLT2i to conventional therapy for AHF reduced all-cause death (odds ratio [OR] 0.75; 95% CI 0.56-0.99; p = 0.049), readmissions for heart failure (HF) (OR 0.54; 95% CI 0.44-0.66; p < 0.001), and the composite of cardiovascular death and readmissions for HF (hazard ratio 0.71; 95% CI 0.60-0.84; p < 0.001). Furthermore, SGLT2i increased mean daily urinary output in liters (mean difference [MD] 0.45; 95% CI 0.03-0.87; p = 0.035) and decreased mean daily doses of loop diuretics in mg of furosemide equivalent (MD -34.90; 95% CI [- 52.58, - 17.21]; p < 0.001) without increasing the incidence worsening renal function (OR 0.75; 95% CI 0.43-1.29; p = 0.290).
CONCLUSION
SGLT2i addition to conventional diuretic therapy reduced all-cause death, readmissions for HF, and the composite of cardiovascular death or readmissions for HF. Moreover, SGLT2i was associated with a higher volume of diuresis with a lower dose of loop diuretics.
Topics: Humans; Diabetes Mellitus, Type 2; Diuretics; Heart Failure; Kidney; Randomized Controlled Trials as Topic; Sodium Potassium Chloride Symporter Inhibitors; Sodium-Glucose Transporter 2 Inhibitors
PubMed: 36592186
DOI: 10.1007/s00392-022-02148-2 -
European Journal of Heart Failure Jun 2023Episodes of worsening symptoms and signs characterize the clinical course of patients with chronic heart failure (HF). These events are associated with poorer quality of...
Worsening of chronic heart failure: definition, epidemiology, management and prevention. A clinical consensus statement by the Heart Failure Association of the European Society of Cardiology.
Episodes of worsening symptoms and signs characterize the clinical course of patients with chronic heart failure (HF). These events are associated with poorer quality of life, increased risks of hospitalization and death and are a major burden on healthcare resources. They usually require diuretic therapy, either administered intravenously or by escalation of oral doses or with combinations of different diuretic classes. Additional treatments may also have a major role, including initiation of guideline-recommended medical therapy (GRMT). Hospital admission is often necessary but treatment in the emergency service or in outpatient clinics or by primary care physicians has become increasingly used. Prevention of first and recurring episodes of worsening HF is an essential component of HF treatment and this may be achieved through early and rapid administration of GRMT. The aim of the present clinical consensus statement by the Heart Failure Association of the European Society of Cardiology is to provide an update on the definition, clinical characteristics, management and prevention of worsening HF in clinical practice.
Topics: Humans; Heart Failure; Angiotensin-Converting Enzyme Inhibitors; Quality of Life; Adrenergic beta-Antagonists; Chronic Disease; Cardiology; Diuretics; Hospitalization
PubMed: 37208936
DOI: 10.1002/ejhf.2874 -
European Journal of Heart Failure Feb 2022Insufficient diuretic response frequently occurs in patients admitted for acute heart failure (HF) and is associated with worse clinical outcomes. Recent studies have... (Randomized Controlled Trial)
Randomized Controlled Trial
AIMS
Insufficient diuretic response frequently occurs in patients admitted for acute heart failure (HF) and is associated with worse clinical outcomes. Recent studies have shown that measuring natriuresis early after hospital admission could reliably identify patients with a poor diuretic response during hospitalization who might require enhanced diuretic treatment. This study will test the hypothesis that natriuresis-guided therapy in patients with acute HF improves natriuresis and clinical outcomes.
METHODS
The Pragmatic Urinary Sodium-based treatment algoritHm in Acute Heart Failure (PUSH-AHF) is a pragmatic, single-centre, randomized, controlled, open-label study, aiming to recruit 310 acute HF patients requiring treatment with intravenous loop diuretics. Patients will be randomized to natriuresis-guided therapy or standard of care. Natriuresis will be determined at set time points after initiation of intravenous loop diuretics, and treatment will be adjusted based on the urinary sodium levels in the natriuresis-guided group using a pre-specified stepwise approach of increasing doses of loop diuretics and the initiation of combination diuretic therapy. The co-primary endpoint is 24-h urinary sodium excretion after start of loop diuretic therapy and a combined endpoint of all-cause mortality or first HF rehospitalization at 6 months. Secondary endpoints include 48- and 72-h sodium excretion, length of hospital stay, and percentage change in N-terminal pro brain natriuretic peptide at 48 and 72 h.
CONCLUSION
The PUSH-AHF study will investigate whether natriuresis-guided therapy, using a pre-specified stepwise diuretic treatment approach, improves natriuresis and clinical outcomes in patients with acute HF.
Topics: Algorithms; Diuretics; Heart Failure; Humans; Natriuresis; Sodium; Sodium Potassium Chloride Symporter Inhibitors
PubMed: 34791756
DOI: 10.1002/ejhf.2385 -
JACC. Heart Failure Mar 2020This study compared combination diuretic strategies in acute heart failure (AHF) complicated by diuretic resistance (DR). (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVES
This study compared combination diuretic strategies in acute heart failure (AHF) complicated by diuretic resistance (DR).
BACKGROUND
Combination diuretic regimens to overcome loop DR are commonly used but with limited evidence.
METHODS
This 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.
RESULTS
The 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).
CONCLUSIONS
In 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).
Topics: Administration, Oral; Aged; Chlorothiazide; Diuretics; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Female; Follow-Up Studies; Furosemide; Heart Failure; Humans; Infusions, Intravenous; Male; Metolazone; Middle Aged; Prospective Studies; Retrospective Studies; Tolvaptan; Treatment Outcome
PubMed: 31838029
DOI: 10.1016/j.jchf.2019.09.012