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JACC. Heart Failure Jan 2024The EMPEROR-Reduced (EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Reduced Ejection Fraction) trial established the efficacy of empagliflozin... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
The EMPEROR-Reduced (EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Reduced Ejection Fraction) trial established the efficacy of empagliflozin in reducing heart failure (HF) outcomes among patients with heart failure with reduced ejection fraction (HFrEF).
OBJECTIVES
The authors examined the outcomes of EMPEROR-Reduced as a function of background diuretic therapy.
METHODS
The EMPEROR-Reduced trial was a double-blind, randomized controlled trial of placebo vs empagliflozin 10 mg among 3,730 HFrEF patients. Herein, the population was stratified into 4 groups: no diuretic and diuretic dose equivalent to furosemide <40, 40, and >40 mg daily at baseline.
RESULTS
A total of 3,656 patients from the EMPEROR-Reduced trial were available for analysis. Of those patients, 482 (13.2%) were receiving no diuretic therapy, and 731 (20.0%), 1,411 (38.6%), and 1,032 (28.2%) were receiving <40 mg, 40 mg, and >40 mg, respectively. The efficacy of empagliflozin on the primary outcome (time to first event of hospitalization for HF or cardiovascular [CV] death) was consistent regardless of background diuretic therapy (>40 mg: HR: 0.88 [95% CI: 0.71-1.10]; 40 mg: HR: 0.65 [95% CI: 0.51-0.82]; <40 mg: HR: 0.65 [95% CI: 0.46-0.92]); no diuretic agents: HR: 0.78 [95% CI: 0.47-1.29]; P = 0.192). Baseline diuretic doses did not influence the effect of empagliflozin on body weight, systolic blood pressure, NT-proBNP, or hematocrit at 52 weeks. The safety profile of empagliflozin vs placebo was unaffected by baseline diuretic dose; however, independently of treatment allocation, total rates of adverse events were higher among patients with higher baseline doses of diuretic agents.
CONCLUSIONS
Empagliflozin exhibits a consistent effect on time to CV death or HF hospitalization and an unaltered safety profile regardless of baseline diuretic therapy. (EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Reduced Ejection Fraction [EMPEROR-Reduced]; NCT03057977).
Topics: Humans; Benzhydryl Compounds; Chronic Disease; Diuretics; Heart Failure; Stroke Volume; Ventricular Dysfunction, Left
PubMed: 37715769
DOI: 10.1016/j.jchf.2023.06.036 -
Medicine Nov 2022Pulmonary hypertension (PH) is a severe form of pulmonary vascular disease that can lead to right heart failure (RHF). Nearly 2-thirds of patients with PH die within 5...
Pulmonary hypertension (PH) is a severe form of pulmonary vascular disease that can lead to right heart failure (RHF). Nearly 2-thirds of patients with PH die within 5 years. Studies suggest that a new diuretic medication, called tolvaptan (TLV), can be used to treat PH. However, there is still insufficient evidence to confirm its effectiveness. Therefore, we investigated the role of TLV in patients with PH. This retrospective study included 73 patients with PH hospitalized in Shanghai Pulmonary Hospital between November 2019 and March 2022. All patients received 7.5 to 15.0 mg of TLV for 3 to 21 days starting at admission, in addition to targeted drugs and traditional diuretic therapy. The outcomes included the blood pressure, urine and water intake volumes, electrolyte concentrations, and renal, liver, and cardiac function indexes before and after TLV treatment. In addition, we assessed the clinical symptoms and adverse reactions during the treatment. After TLV treatment, the water intake and urine volumes significantly increased, and body weight, diastolic blood pressure (DBP) and mean arterial pressure significantly decreased. Total bilirubin, direct bilirubin, N-terminal pro-brain natriuretic peptide, and serum uric acid (UA) levels after TLV treatment were significantly lower than before treatment. After TLV treatment, dyspnea significantly improved in 71 of 73 patients, and lower limb edema disappeared in 42 of 53 patients. No obvious adverse reactions occurred during the TLV treatment period. These results suggest that adding TLV to targeted drug and traditional diuretic therapies is effective for patients with PH. However, more data are required to support these findings.
Topics: Humans; Tolvaptan; Hypertension, Pulmonary; Retrospective Studies; Uric Acid; China; Diuretics; Bilirubin
PubMed: 36451399
DOI: 10.1097/MD.0000000000031587 -
Cardiovascular Diabetology Aug 2023Patients with heart failure have increased cardiac filling pressures, circulating natriuretic peptides, and physical signs of fluid retention, which are related to... (Review)
Review
Patients with heart failure have increased cardiac filling pressures, circulating natriuretic peptides, and physical signs of fluid retention, which are related to sodium retention by the kidneys and are alleviated by conventional diuretics. Sodium-glucose cotransporter 2 (SGLT2) inhibitors interfere with sodium and glucose reabsorption in the proximal renal tubule, but they evoke a marked counterregulatory activation of sodium and water reabsorption in distal nephron segments, which opposes and negates any diuretic effect. Nevertheless, it has been postulated that SGLT2 inhibitors modulate the volume set point, leading selectively to decongestion in patients with fluid overload. This hypothesis was tested in a review of 15 randomized controlled trials of SGLT2 inhibitors in patients with heart failure, with 7 trials focusing on urinary volume within the first week, and 8 trials focusing on objective decongestion at 12 weeks. In trials < 1 week, SGLT2 inhibition increased urine volume in the first 24 h, but typically without a change in urinary sodium excretion, and this diuresis was not sustained. In 8 trials of 12 weeks' duration, none reported alleviation of edema, ascites or pulmonary rales. The 2 trials that evaluated changes in left ventricular filling pressure noted no or small changes (1-2 mm Hg); the two trials that measured interstitial lung water or total blood volume found no effect; and 6 of the 7 trials found no decrease in circulating natriuretic peptides. Therefore, randomized controlled trials do not indicate that SGLT2 inhibitors produce a durable natriuresis or objective decongestion in patients with heart failure.
Topics: Humans; Diuretics; Heart Failure; Natriuresis; Randomized Controlled Trials as Topic; Sodium-Glucose Transporter 2 Inhibitors
PubMed: 37533009
DOI: 10.1186/s12933-023-01946-w -
European Journal of Heart Failure Jul 2021To study loop diuretic response and effect of loop diuretic omission in ambulatory heart failure (HF) patients on chronic low-dose loop diuretics.
AIMS
To study loop diuretic response and effect of loop diuretic omission in ambulatory heart failure (HF) patients on chronic low-dose loop diuretics.
METHODS AND RESULTS
Urine collections were performed on two consecutive days in 40 ambulatory HF patients with 40-80 mg furosemide (day 1 with loop diuretic; day 2 without loop diuretic). Three phases were collected each day: (i) first 6 h; (ii) rest of the day; and (iii) night. On the day of loop diuretic intake, the total natriuresis was 125.9 (86.9-155.0) mmol/24 h and urine output was 1650 (1380-2025) mL/24 h. There was a clear loop diuretic response with a natriuresis of 9.4 (6.7-15.9) mmol/h and a urine output of 117 (83-167) mL/h during the first 6 h, followed by a significant drop in natriuresis and urine output during the rest of the day [2.6 (1.8-4.8) mmol/h and 55 (33-71) mL/h] and night [2.2 (1.6-3.5) mmol/h and 44 (34-73) mL/h]. On day 2, after loop diuretic omission, the natriuresis and urine output remained similarly low the entire day, resulting in a 50% reduction in natriuresis [55.1 (33.5-77.7) mmol/24 h; P < 0.001] and a 31% reduction in urine output [1035 (875-1425) mL/24 h; P < 0.001] compared with the day of loop diuretic intake.
CONCLUSION
Patients with HF on chronic loop diuretic treatment still have a clear diuretic response phase, while loop diuretic omission leads to a significant drop in natriuresis and urine output, arguing against routine cessation of low-dose loop diuretics.
Topics: Diuretics; Furosemide; Heart Failure; Humans; Natriuresis; Sodium Potassium Chloride Symporter Inhibitors
PubMed: 33641220
DOI: 10.1002/ejhf.2145 -
Current Heart Failure Reports Apr 2024Fluid retention or congestion is a major cause of symptoms, poor quality of life, and adverse outcome in patients with heart failure (HF). Despite advances in... (Review)
Review
PURPOSE OF REVIEW
Fluid retention or congestion is a major cause of symptoms, poor quality of life, and adverse outcome in patients with heart failure (HF). Despite advances in disease-modifying therapy, the mainstay of treatment for congestion-loop diuretics-has remained largely unchanged for 50 years. In these two articles (part I: loop diuretics and part II: combination therapy), we will review the history of diuretic treatment and current trial evidence for different diuretic strategies and explore potential future directions of research.
RECENT FINDINGS
We will assess recent trials, including DOSE, TRANSFORM, ADVOR, CLOROTIC, OSPREY-AHF, and PUSH-AHF, and assess how these may influence current practice and future research. There are few data on which to base diuretic therapy in clinical practice. The most robust evidence is for high-dose loop diuretic treatment over low-dose treatment for patients admitted to hospital with HF, yet this is not reflected in guidelines. There is an urgent need for more and better research on different diuretic strategies in patients with HF.
Topics: Humans; Heart Failure; Sodium Potassium Chloride Symporter Inhibitors; Quality of Life; Diuretics; Hospitalization
PubMed: 38300391
DOI: 10.1007/s11897-024-00644-2 -
Journal of the American College of... Apr 2024Sodium-glucose cotransporter 2 inhibitors are believed to improve cardiac outcomes due to their osmotic diuretic potential. (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Sodium-glucose cotransporter 2 inhibitors are believed to improve cardiac outcomes due to their osmotic diuretic potential.
OBJECTIVES
The goal of this study was to test the hypothesis that vasopressin-driven urine concentration overrides the osmotic diuretic effect of glucosuria induced by dapagliflozin treatment.
METHODS
DAPA-Shuttle1 (Hepato-renal Regulation of Water Conservation in Heart Failure Patients With SGLT-2 Inhibitor Treatment) was a single-center, double-blind, randomized, placebo-controlled trial, in which patients with chronic heart failure NYHA functional classes I/II and reduced ejection fraction were randomly assigned to receive dapagliflozin 10 mg daily or placebo (1:1) for 4 weeks. The primary endpoint was change from baseline in urine osmolyte concentration. Secondary endpoints included changes in copeptin levels and solute free water clearance.
RESULTS
Thirty-three randomized, sodium-glucose cotransporter 2 inhibitor-naïve participants completed the study, 29 of whom (placebo: n = 14; dapagliflozin: n = 15) provided accurate 24-hour urine collections (mean age 59 ± 14 years; left ventricular ejection fraction 31% ± 9%). Dapagliflozin treatment led to an isolated increase in urine glucose excretion by 3.3 mmol/kg/d (95% CI: 2.51-4.04; P < 0.0001) within 48 hours (early) which persisted after 4 weeks (late; 2.7 mmol/kg/d [95% CI: 1.98-3.51]; P < 0.0001). Dapagliflozin treatment increased serum copeptin early (5.5 pmol/L [95% CI: 0.45-10.5]; P < 0.05) and late (7.8 pmol/L [95% CI: 2.77-12.81]; P < 0.01), leading to proportional reductions in free water clearance (early: -9.1 mL/kg/d [95% CI: -14 to -4.12; P < 0.001]; late: -11.0 mL/kg/d [95% CI: -15.94 to -6.07; P < 0.0001]) and elevated urine concentrations (late: 134 mmol/L [95% CI: 39.28-229.12]; P < 0.01). Therefore, urine volume did not significantly increase with dapagliflozin (mean difference early: 2.8 mL/kg/d [95% CI: -1.97 to 7.48; P = 0.25]; mean difference late: 0.9 mL/kg/d [95% CI: -3.83 to 5.62]; P = 0.70).
CONCLUSIONS
Physiological-adaptive water conservation eliminated the expected osmotic diuretic potential of dapagliflozin and thereby prevented a glucose-driven increase in urine volume of approximately 10 mL/kg/d · 75 kg = 750 mL/kg/d. (Hepato-renal Regulation of Water Conservation in Heart Failure Patients With SGLT-2 Inhibitor Treatment [DAPA-Shuttle1]; NCT04080518).
Topics: Aged; Humans; Middle Aged; Benzhydryl Compounds; Conservation of Water Resources; Diuresis; Diuretics, Osmotic; Glucosides; Heart Failure; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors; Stroke Volume; Ventricular Function, Left; Water
PubMed: 38599715
DOI: 10.1016/j.jacc.2024.02.020 -
Methodist DeBakey Cardiovascular Journal 2022Heart failure can lead to renal impairment, an interaction now termed "cardiorenal syndrome." The prevalent physiological explanation for the renal impairment that... (Review)
Review
Heart failure can lead to renal impairment, an interaction now termed "cardiorenal syndrome." The prevalent physiological explanation for the renal impairment that accompanies heart failure centers around the forward failure hypothesis, which emphasizes the role of left ventricular dysfunction in causing edema, and the backward failure hypothesis, which singles out venous congestion as the dominant mechanism of edema and reduced glomerular filtration rate. In this review, we provide an appraisal on venous congestion, an extremely important contributor that has received little attention. We also summarize the pharmacology of loop diuretics, explain current understanding of diuretic resistance, and address controversies regarding decongestive treatments.
Topics: Cardio-Renal Syndrome; Diuretics; Heart Failure; Humans; Hyperemia; Kidney; Sodium Potassium Chloride Symporter Inhibitors
PubMed: 36132580
DOI: 10.14797/mdcvj.1121 -
Current Heart Failure Reports Dec 2023With the widespread implementation of contemporary disease-modifying heart failure therapy, the rates of normalization of ejection fraction are continuously increasing.... (Review)
Review
PURPOSE OF REVIEW
With the widespread implementation of contemporary disease-modifying heart failure therapy, the rates of normalization of ejection fraction are continuously increasing. The TRED-HF trial confirmed that heart failure remission rather than complete recovery is typical in patients with dilated cardiomyopathy who respond to therapy. The present review outlines key points related to the management and knowledge gaps of this growing patient group, focusing on patients with non-ischaemic dilated cardiomyopathy.
RECENT FINDINGS
There is substantial heterogeneity among patients with normalized ejection fraction. The specific etiology is likely to affect the outcome, although a multiple-hit phenotype is frequent and may not be identified without comprehensive characterization. A monogenic or polygenic genetic susceptibility is common. Ongoing pathophysiological processes may be unraveled with advanced cardiac imaging, biomarkers, multi-omics, and machine learning technologies. There are limited studies that have investigated the withdrawal of specific heart failure therapies in these patients. Diuretics may be safely withdrawn if there is no evidence of congestion, while continued therapy with at least some disease-modifying therapy is likely to be required to reduce myocardial workload and sustain remission for the vast majority. Understanding the underlying disease mechanisms of patients with normalized ejection fraction is crucial in identifying markers of myocardial relapse and guiding individualized therapy in the future. Ongoing clinical trials should inform personalized approaches to therapy.
Topics: Humans; Biomarkers; Cardiomyopathy, Dilated; Cardiotonic Agents; Diuretics; Heart Failure; Stroke Volume; Ventricular Function, Left; Randomized Controlled Trials as Topic
PubMed: 37999902
DOI: 10.1007/s11897-023-00636-8 -
Circulation Sep 2020In the DAPA-HF trial (Dapagliflozin and Prevention of Adverse-Outcomes in Heart Failure), the sodium-glucose cotransporter 2 inhibitor dapagliflozin reduced the risk of... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
In the DAPA-HF trial (Dapagliflozin and Prevention of Adverse-Outcomes in Heart Failure), the sodium-glucose cotransporter 2 inhibitor dapagliflozin reduced the risk of worsening heart failure and death in patients with heart failure and reduced ejection fraction. We examined the efficacy and tolerability of dapagliflozin in relation to background diuretic treatment and change in diuretic therapy after randomization to dapagliflozin or placebo.
METHODS
We examined the effects of study treatment in the following subgroups: no diuretic and diuretic dose equivalent to furosemide <40, 40, and >40 mg daily at baseline. We examined the primary composite end point of cardiovascular death or a worsening heart failure event and its components, all-cause death and symptoms.
RESULTS
Of 4616 analyzable patients, 736 (15.9%) were on no diuretic, 1311 (28.4%) were on <40 mg, 1365 (29.6%) were on 40 mg, and 1204 (26.1%) were taking >40 mg. Compared with placebo, dapagliflozin reduced the risk of the primary end point across each of these subgroups: hazard ratios were 0.57 (95% CI, 0.36-0.92), 0.83 (95% CI, 0.63-1.10), 0.77 (95% CI, 0.60-0.99), and 0.78 (95% CI, 0.63-0.97), respectively ( for interaction=0.61). The hazard ratio in patients taking any diuretic was 0.78 (95% CI, 0.68-0.90). Improvements in symptoms and treatment toleration were consistent across the diuretic subgroups. Diuretic dose did not change in most patients during follow-up, and mean diuretic dose did not differ between the dapagliflozin and placebo groups after randomization.
CONCLUSIONS
The efficacy and safety of dapagliflozin were consistent across the diuretic subgroups examined in DAPA-HF. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03036124.
Topics: Aged; Aged, 80 and over; Benzhydryl Compounds; Diuretics; Female; Glucosides; Heart Failure; Humans; Male; Middle Aged; Stroke Volume
PubMed: 32673497
DOI: 10.1161/CIRCULATIONAHA.120.047077 -
JACC. Heart Failure Jun 2022Up to 20% of patients in heart failure with reduced ejection fraction (HFrEF) trials are not taking diuretic agents at baseline, but little is known about them.
BACKGROUND
Up to 20% of patients in heart failure with reduced ejection fraction (HFrEF) trials are not taking diuretic agents at baseline, but little is known about them.
OBJECTIVES
The aim of this study was to examine outcomes in patients with HFrEF not taking diuretic medications and after diuretic medications are started.
METHODS
Patient characteristics and outcomes were compared between patients taking or not taking diuretic drugs at baseline in the ATMOSPHERE (Aliskiren Trial of Minimizing Outcomes for Patients With Heart Failure) and PARADIGM-HF (Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure Trial) trials combined. Patients starting diuretic medications were also compared with those remaining off diuretic drugs during follow-up. Symptoms (Kansas City Cardiomyopathy Questionnaire Clinical Summary Score [KCCQ-CSS]), hospitalization for worsening heart failure (HF), mortality, and kidney function (estimated glomerular filtration rate slope) were examined.
RESULTS
At baseline, the 3,079 of 15,415 patients (20%) not taking diuretic medications had a less severe HF profile, less neurohumoral activation, and better kidney function. They were less likely to experience the primary outcome (hospitalization for HF or cardiovascular death) than patients taking diuretic agents (adjusted HR: 0.77; 95% CI: 0.74-0.80; P < 0.001) and death of any cause. Commencement of a diuretic drug was associated with higher subsequent risk for death (adjusted HR: 2.05; 95% CI: 1.99-2.11; P < 0.001) and greater decreases in KCCQ-CSS and estimated glomerular filtration rate. The 5 strongest predictors of initiation of diuretic medications were higher N-terminal pro-B-type natriuretic peptide, higher body mass index, older age, history of diabetes, and worse KCCQ-CSS. In PARADIGM-HF, fewer patients who were treated with sacubitril/valsartan commenced diuretic agents (OR: 0.72; 95% CI: 0.58-0.88; P = 0.002).
CONCLUSIONS
Patients with HFrEF not taking diuretic medications and those who remained off them had better outcomes than patients treated with diuretic agents or who commenced them.
Topics: Aminobutyrates; Angiotensin Receptor Antagonists; Biphenyl Compounds; Diuretics; Heart Failure; Humans; Prospective Studies; Stroke Volume; Tetrazoles; Ventricular Dysfunction, Left
PubMed: 35654526
DOI: 10.1016/j.jchf.2022.01.020