Effect of Torsemide Versus Furosemide on Symptoms and Quality of Life Among Patients Hospitalized for Heart Failure: The TRANSFORM-HF Randomized Clinical Trial.

BACKGROUND: Loop diuretics are a primary therapy for the symptomatic treatment of heart failure (HF), but whether torsemide improves patient symptoms and quality of life better than furosemide remains unknown. As prespecified secondary end points, the TRANSFORM-HF trial (Torsemide Comparison With Furosemide for Management of Heart Failure) compared the effect of torsemide versus furosemide on patient-reported outcomes among patients with HF. METHODS: TRANSFORM-HF was an open-label, pragmatic, randomized trial of 2859 patients hospitalized for HF (regardless of ejection fraction) across 60 hospitals in the United States. Patients were randomly assigned in a 1:1 ratio to a loop diuretic strategy of torsemide or furosemide with investigator-selected dosage. This report examined effects on prespecified secondary end points, which included Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS; assessed as adjusted mean difference in change from baseline; range, 0-100 with 100 indicating best health status; clinically important difference, ≥5 points) and Patient Health Questionnaire-2 (range, 0-6; score ≥3 supporting evaluation for depression) over 12 months. RESULTS: Baseline data were available for 2787 (97.5%) patients for KCCQ-CSS and 2624 (91.8%) patients for Patient Health Questionnaire-2. Median (interquartile range) baseline KCCQ-CSS was 42 (27-60) in the torsemide group and 40 (24-59) in the furosemide group. At 12 months, there was no significant difference between torsemide and furosemide in change from baseline in KCCQ-CSS (adjusted mean difference, 0.06 [95% CI, -2.26 to 2.37]; P=0.96) or the proportion of patients with Patient Health Questionnaire-2 score ≥3 (15.1% versus 13.2%: P=0.34). Results for KCCQ-CSS were similar at 1 month (adjusted mean difference, 1.36 [95% CI, -0.64 to 3.36]; P=0.18) and 6-month follow-up (adjusted mean difference, -0.37 [95% CI, -2.52 to 1.78]; P=0.73), and across subgroups by ejection fraction phenotype, New York Heart Association class at randomization, and loop diuretic agent before hospitalization. Irrespective of baseline KCCQ-CSS tertile, there was no significant difference between torsemide and furosemide on change in KCCQ-CSS, all-cause mortality, or all-cause hospitalization. CONCLUSIONS: Among patients discharged after hospitalization for HF, a strategy of torsemide compared with furosemide did not improve symptoms or quality of life over 12 months. The effects of torsemide and furosemide on patient-reported outcomes were similar regardless of ejection fraction, previous loop diuretic use, and baseline health status. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03296813.

Levels of Albumin and Impact on Loop Diuretic and Albumin Co-administration in Heart Failure.

ABSTRACT: Management of heart failure (HF) requires the use of loop diuretics to relieve congestion and improve symptoms. When loop diuretics alone fail to induce adequate diuresis, albumin has been proposed to enhance loop diuretic delivery and promote redistribution of fluid for excretion by the kidneys. Despite the theoretical benefits of albumin, studies suggesting its benefit in HF are scarce and the co-administration of loop diuretics and albumin remains controversial. This retrospective, observational study evaluated patients with HF 18 years or older who received concomitant intravenous loop diuretic and albumin administration. The primary objective was to evaluate the association of serum albumin level with urine output (UOP) in hospitalized patients with HF who received concomitant albumin and loop diuretic therapy. Secondary endpoints included total weight loss after 72 hours, and ICU and hospital lengths of stay. In total, 276 patients were included for analysis. There was no association between initial serum albumin level and 72-hour UOP (coefficient -623.1, 95% confidence interval -1558.6 to 312.4; P = 0.191) or weight difference at 72 hours (coefficient -1.0, 95% confidence interval -2.4 to 0.3; P = 0.131). Lower albumin levels were associated with longer ICU ( P = 0.034) and hospital ( P = 0.039) lengths of stay. Concomitant thiazide diuretic use and increasing loop diuretic doses were associated with increased 72-hour UOP. The results of our study suggests that providers should avoid using baseline albumin levels as guidance for albumin dosing in HF. Given the lack of comparator groups, larger randomized controlled trials should be done to provide a definitive role for albumin to enhance diuresis in patients with HF on intravenous loop diuretics.

Metolazone Versus Chlorothiazide in Acute Heart Failure Patients With Diuretic Resistance and Renal Dysfunction: A Retrospective Cohort Study.

ABSTRACT: Guidelines recommend intravenous loop diuretics as first-line therapy for patients hospitalized with acute heart failure (AHF) and volume overload. Additional agents can be used for augmentation, but there is limited guidance on agent selection. The study objective was to determine if chlorothiazide or metolazone is associated with differences in diuretic efficacy or safety in loop diuretic-resistant patients with AHF and renal dysfunction (eGFR <45 mL/min/1.73 m²). We conducted a multicenter, retrospective cohort study of patients hospitalized with AHF and renal dysfunction who received metolazone or chlorothiazide in addition to intravenous loop diuretics. The primary end point was a comparison of 24-hour urine output (UOP) between the 24 hours before and after thiazide administration. Secondary and safety end points included weight change, requirement for vasopressors or inotropes, electrolyte abnormalities, and changes in renal function. A total of 221 patients were included. The mean daily diuretic doses were chlorothiazide 632 mg and metolazone 7 mg. The mean 24-hour UOP increased more among chlorothiazide-treated (from 1668 mL to 3826 mL) versus metolazone-treated patients (from 1672 mL to 2834 mL) ( P < 0.001) after the addition of the second diuretic. Statistically significant reductions in serum creatinine were observed in the chlorothiazide group following 72 hours of treatment ( P = 0.016). More hypomagnesemia was observed in the chlorothiazide group; no differences in other electrolytes or changes in weight were observed. Overall, chlorothiazide was associated with a greater increase in 24-hour UOP than metolazone without an excess of potassium or serum creatinine derangements. However, weight changes did not differ significantly between groups. Future prospective studies are needed to confirm potential differences in diuretic response and safety.

Effect of dapagliflozin on readmission and loop diuretics use in patients with acute heart failure: a retrospective propensity score-matched cohort study.

BACKGROUND: The efficacy of dapagliflozin in patients with acute heart failure remains unclear. OBJECTIVE: To investigate the impact of dapagliflozin (DAPA) on loop diuretics use and 90-day readmission in patients with acute heart failure. METHODS: In a retrospective cohort study, patients diagnosed with acute heart failure or chronic heart failure with acute exacerbation admitted to Fuyang People's Hospital from January 2021 to April 2023, this study used DAPA (at a dose of 10 mg once daily) in combination with standard treatment. The patients were divided into DAPA group and DAPA-Free group based on whether they used DAPA in acute heart failure. To minimize the influence of confounding factors and ensure comparability between groups, we used propensity score matching (PSM). RESULTS: A total of 399 patients were included, with 206 patients (51.63%) in the DAPA group and 193 patients (48.37%) in the DAPA-Free group. PSM produced 160 pairs. After PSM, there were no statistically significant differences between the DAPA and DAPA-Free groups in terms of readmission of all causes (16.88% vs. 18.12%, OR 0.9141, 95% CI 0.5385-1.552, log rank P = 0.739) or readmission for heart failure (11.88% vs. 15.0%, OR 0.9077, 95% CI 0.4441-1.469, log rank P = 0.484) after 90-day follow-up. Patients in the DAPA group had a lower mean daily dose of intravenous loop diuretics compared to the DAPA-Free group (20 mg/d vs. 30.00 mg/d, P<0.001), lower total loop diuretic dose during hospitalization (106.06 ± 31.23 mg vs. 144.50 ± 45.39 mg, P = 0.038) and a decreased number of diuretic types used (11.88% vs. 23.12%, P = 0.008). CONCLUSIONS: DAPA reduced the dose of intravenous loop diuretics. However, it did not improve all-cause readmission for 90 days or readmission for heart failure after discharge.

Prediction of cardiac surgery associated acute kidney injury using response to loop diuretic and urine neutrophil gelatinase associated lipocalin.

BACKGROUND: Cardiac surgery associated acute kidney injury (CS-AKI) is common. Urine response to loop diuretic and urine neutrophil gelatinase associated lipocalin (uNGAL) are separately associated with CS-AKI. We aimed to determine whether urine response to loop diuretic and uNGAL together were associated with postoperative day 2-4 CS-AKI. METHODS: Two-center prospective observational study (ages 0-18 years). uNGAL (8-12 h after admission) (ng/mL) and urine response to loop diuretic (6 h for bolus furosemide and 12 h for infusion bumetanide) (mL/kg/hr) were measured. All diuretic doses were converted to furosemide equivalents. The primary outcome was day 2-4 CS-AKI. Patients were sub-phenotyped using a priori cutoffs (uNGAL + ≥ 100 ng/mL and UOP + < 1.5 mL/kg/hr) and optimal cutoffs (uNGAL + ≥ 127 ng/mL and UOP + ≤ 0.79 mL/kg/hr): 1) uNGAL-/UOP-, 2) uNGAL-/UOP + , 3) uNGAL + /UOP-, and 4) uNGAL + /UOP + . Multivariable regression was used to assess the association of uNGAL, UOP and each sub-phenotype with outcomes. RESULTS: 476 patients were included. CS-AKI occurred in 52 (10.9%). uNGAL was associated with 2.59-fold greater odds (95%CI: 1.52-4.41) of CS-AKI. UOP was not associated with CS-AKI. Compared with uNGAL + alone, uNGAL + /UOP + improved prediction of CS-AKI using a priori and optimal cutoffs respectively (AUC 0.70 vs. 0.75). Both uNGAL + /UOP + (IQR OR:4.63, 95%CI: 1.74-12.32) and uNGAL + /UOP- (IQR OR:5.94, 95%CI: 2.09-16.84) were associated with CS-AKI when compared with uNGAL-/UOP-. CONCLUSIONS: uNGAL is associated with CS-AKI. The sub-phenotype association was largely driven by uNGAL. Future studies standardizing diuretic dose and timing may be needed to refine the combined performance for clinical decision making.

Ototoxic and nephrotoxic drugs in neonatal intensive care units: results of a Spanish and Italian survey.

Neonates face heightened susceptibility to drug toxicity, often exposed to off-label medications with dosages extrapolated from adult or pediatric studies. Premature infants in Neonatal Intensive Care Units (NICUs) are particularly at risk due to underdeveloped pharmacokinetics and exposure to multiple drugs. The study aimed to survey commonly used medications with a higher risk of ototoxicity and nephrotoxicity in Spanish and Italian neonatal units. A prospective cross-sectional study was conducted in Italian and Spanish neonatal units using a web-based survey with 43 questions. A modified Delphi method involved experts refining the survey through online consensus. Ethical approval was obtained, and responses were collected from January to July 2023. The survey covered various aspects, including drug-related ototoxic and nephrotoxic management, hearing screening, and therapeutic drug monitoring. Responses from 131 participants (35.9% from Spain and 64.1% from Italy) revealed awareness of drug toxicity risks. Varied practices were observed in hearing screening protocols, and a high prevalence of ototoxic and nephrotoxic drug use, including aminoglycosides (100%), vancomycin (70.2%), loop diuretics (63.4%), and ibuprofen (62.6%). Discrepancies existed in guideline availability and adherence, with differences between Italy and Spain in therapeutic drug monitoring practices. CONCLUSIONS: The study underscores the need for clinical guidelines and uniform practices in managing ototoxic and nephrotoxic drugs in neonatal units. Awareness is high, but inconsistencies in practices indicate a necessity for standardization, including the implementation of therapeutic drug monitoring and the involvement of clinical pharmacologists. Addressing these issues is crucial for optimizing neonatal care in Southern Europe. WHAT IS KNOWN: • Neonates in intensive care face a high risk of nephrotoxicity and ototoxicity from drugs like aminoglycosides, vancomycin, loop diuretics, and ibuprofen. • Therapeutic drug monitoring is key for managing these risks, optimizing dosing for efficacy and minimizing side effects. WHAT IS NEW: • NICUs in Spain and Italy show high drug toxicity awareness but differ in ototoxic/nephrotoxic drug management. • Urgent need for standard guidelines and practices to address nephrotoxic risks from aminoglycosides, vancomycin, loop diuretics, and ibuprofen.

Continuous infusion versus bolus injection of loop diuretics for acute heart failure.

BACKGROUND: Acute heart failure (AHF) is new onset of, or a sudden worsening of, chronic heart failure characterised by congestion in about 95% of cases or end-organ hypoperfusion in 5% of cases. Treatment often requires urgent escalation of diuretic therapy, mainly through hospitalisation. This Cochrane review evaluated the efficacy of intravenous loop diuretics strategies in treating AHF in individuals with New York Heart Association (NYHA) classification III or IV and fluid overload. OBJECTIVES: To assess the effects of intravenous continuous infusion versus bolus injection of loop diuretics for the initial treatment of acute heart failure in adults. SEARCH METHODS: We identified trials through systematic searches of bibliographic databases and in clinical trials registers including CENTRAL, MEDLINE, Embase, CPCI-S on the Web of Science, ClinicalTrials.gov, the World Health Organization (WHO) International Clinical Trials Registry platform (ICTRP), and the European Union Trials register. We conducted reference checking and citation searching, and contacted study authors to identify additional studies. The latest search was performed on 29 February 2024. SELECTION CRITERIA: We included randomised controlled trials (RCTs) involving adults with AHF, NYHA classification III or IV, regardless of aetiology or ejection fraction, where trials compared intravenous continuous infusion of loop diuretics with intermittent bolus injection in AHF. We excluded trials with chronic stable heart failure, cardiogenic shock, renal artery stenosis, or end-stage renal disease. Additionally, we excluded studies combining loop diuretics with hypertonic saline, inotropes, vasoactive medications, or renal replacement therapy and trials where diuretic dosing was protocol-driven to achieve a target urine output, due to confounding factors. DATA COLLECTION AND ANALYSIS: Two review authors independently screened papers for inclusion and reviewed full-texts. Outcomes included weight loss, all-cause mortality, length of hospital stay, readmission following discharge, and occurrence of acute kidney injury. We performed risk of bias assessment and meta-analysis where data permitted and assessed certainty of the evidence. MAIN RESULTS: The review included seven RCTs, spanning 32 hospitals in seven countries in North America, Europe, and Asia. Data collection ranged from eight months to six years. Following exclusion of participants in subgroups with confounding treatments and different clinical settings, 681 participants were eligible for review. These additional study characteristics, coupled with our strict inclusion and exclusion criteria, improve the applicability of the body of the evidence as they reflect real-world clinical practice. Meta-analysis was feasible for net weight loss, all-cause mortality, length of hospital stay, readmission, and acute kidney injury. Literature review and narrative analysis explored daily fluid balance; cardiovascular mortality; B-type natriuretic peptide (BNP) change; N-terminal-proBNP change; and adverse incidents such as ototoxicity, hypotension, and electrolyte imbalances. Risk of bias assessment revealed two studies with low overall risk, four with some concerns, and one with high risk. All sensitivity analyses excluded trials at high risk of bias. Only narrative analysis was conducted for 'daily fluid balance' due to diverse data presentation methods across two studies (169 participants, the evidence was very uncertain about the effect). Results of narrative analysis varied. For instance, one study reported higher daily fluid balance within the first 24 hours in the continuous infusion group compared to the bolus injection group, whereas there was no difference in fluid balance beyond this time point. Continuous intravenous infusion of loop diuretics may result in mean net weight loss of 0.86 kg more than bolus injection of loop diuretics, but the evidence is very uncertain (mean difference (MD) 0.86 kg, 95% confidence interval (CI) 0.44 to 1.28; 5 trials, 497 participants; P < 0.001, I2 = 21%; very low-certainty evidence). Importantly, sensitivity analysis excluding trials with high risk of bias showed there was insufficient evidence for a difference in bodyweight loss between groups (MD 0.70 kg, 95% CI -0.06 to 1.46; 3 trials, 378 participants; P = 0.07, I2 = 0%). There may be little to no difference in all-cause mortality between continuous infusion and bolus injection (risk ratio (RR) 1.53, 95% CI 0.81 to 2.90; 5 trials, 530 participants; P = 0.19, I2 = 4%; low-certainty evidence). Despite sensitivity analysis, the direction of the evidence remained unchanged. No trials measured cardiovascular mortality. There may be little to no difference in the length of hospital stay between continuous infusion and bolus injection of loop diuretics, but the evidence is very uncertain (MD -1.10 days, 95% CI -4.84 to 2.64; 4 trials, 211 participants; P = 0.57, I2 = 88%; very low-certainty evidence). Sensitivity analysis improved heterogeneity; however, the direction of the evidence remained unchanged. There may be little to no difference in the readmission to hospital between continuous infusion and bolus injection of loop diuretics (RR 0.85, 95% CI 0.63 to 1.16; 3 trials, 400 participants; P = 0.31, I2 = 0%; low-certainty evidence). Sensitivity analysis continued to show insufficient evidence for a difference in the readmission to hospital between groups. There may be little to no difference in the occurrence of acute kidney injury as an adverse event between continuous infusion and bolus injection of intravenous loop diuretics (RR 1.02, 95% CI 0.70 to 1.49; 3 trials, 491 participants; P = 0.92, I2 = 0%; low-certainty evidence). Sensitivity analysis continued to show that continuous infusion may make little to no difference on the occurrence of acute kidney injury as an adverse events compared to the bolus injection of intravenous loop diuretics. AUTHORS' CONCLUSIONS: Analysis of available data comparing two delivery methods of diuretics in acute heart failure found that the current data are insufficient to show superiority of one strategy intervention over the other. Our findings were based on trials meeting stringent inclusion and exclusion criteria to ensure validity. Despite previous reviews suggesting advantages of continuous infusion over bolus injections, our review found insufficient evidence to support or refute this. However, our review, which excluded trials with clinical confounders and RCTs with high risk of bias, offers the most robust conclusion to date.

Effects of Early Empagliflozin Initiation on Diuresis and Kidney Function in Patients With Acute Decompensated Heart Failure (EMPAG-HF).

BACKGROUND: Effective diuretic regimens using loop diuretics in patients with acute decompensated heart failure are often limited by the development of worsening kidney function. Sodium-glucose cotransporter-2 inhibitors induce glucosuria and sodium excretion with nephroprotective effects in patients with stable heart failure but their role in acute decompensated heart failure is unclear. METHODS: In this single-center, prospective, double-blind, placebo-controlled, randomized study, we randomly assigned patients with acute decompensated heart failure to empagliflozin 25 mg daily or placebo in addition to standard decongestive treatments that included loop diuretics. The primary end point was cumulative urine output over 5 days. Secondary end points included diuretic efficiency, dynamics in markers of kidney function and injury, and NT-proBNP (N-terminal pro-B-type natriuretic peptide). RESULTS: Sixty patients were randomized within 12 hours of hospitalization for acute decompensated heart failure. Addition of empagliflozin daily to standard medical treatment of acute decompensated heart failure resulted in a 25% increase in cumulative urine output over 5 days (median 10.8 versus 8.7 L mL in placebo, group difference estimation 2.2 L [95% CI, 8.4 to 3.6]; P=0.003). Empagliflozin increased diuretic efficiency compared with placebo (14.1 mL urine per milligram furosemide equivalent [95% CI, 0.6-27.7]; P=0.041) without affecting markers of renal function (estimated glomerular filtration rate, 51±19 versus 54±17 mL/min per 1.73 m²; P=0.599) or injury (total urinary protein, 492±845 versus 503±847 mg/g creatinine; P=0.975; and urinary α1-microglobulin, 55.4±38.6 versus 31.3±33.6 mg/g creatinine; P=0.066) with more pronounced decrease in NT-proBNP in the empagliflozin group compared with placebo (-1861 versus -727.2 pg/mL after 5 days; quotient in slope, 0.89 [95% CI, 0.83-0.95]; P<0.001). There were no differences in the incidence of safety events between groups. CONCLUSIONS: Early addition of empagliflozin to standard diuretic therapy increases urine output without affecting renal function in patients with acute decompensated heart failure. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT04049045.

Women on diuretics have a higher risk of hospital admission because of hyponatremia than men.

PURPOSE: Recent studies suggest that women are more susceptible to diuretic-induced hyponatremia resulting in hospital admission than men. The aim of this study was to confirm whether these sex differences in hyponatremia-related hospital admissions in diuretic users remain after adjusting for several confounding variables such as age, dose, and concurrent medication. METHODS: In a case-control design nested in diuretic users, cases of hyponatremia associated hospital admissions between 2005 and 2017 were identified from the PHARMO Data Network. Cases were 1:10 matched to diuretic users as controls. Odds ratios (OR) with 95%CIs were calculated for women versus men and adjusted for potential confounders (age, number of diuretics, other hyponatremia-inducing drugs, chronic disease score) using unconditional logistic regression analysis. A subgroup analysis was performed for specific diuretic groups (thiazides, loop diuretics and aldosterone antagonists). RESULTS: Women had a statistically significantly higher risk of a hospital admission associated with hyponatremia than men while using diuretics (OR 1.86, 95%CI 1.64-2.11). Adjusting for the potential confounders resulted in an increased risk for women compared to men (ORadj 2.65, 95% CI 2.31-3.04). This higher risk in women was also seen in the three subgroup analyses after adjustment. CONCLUSION: Our findings show a higher risk of hyponatremia-related hospital admission in women than men while using diuretics. Further research is needed to understand the underlying mechanism of this sex difference to be able to provide sex-specific recommendations.

Diuretics in pediatrics.

Diuretics are frequently prescribed drugs and help managing several pathological conditions, including acute and chronic kidney disease, nephrotic syndrome, congestive heart failure, ascites, systemic and pulmonary hypertension. Diuretic classes include among others osmotic diuretics and carboanhydrase inhibitors, loop diuretics, thiazides, and potassium-sparing diuretics. In this educational article, we aim at reviewing indications, mechanisms of action, and side effects, as well as basic pharmacokinetics considerations and data on diuretics in children, supporting practicing clinicians in choosing (and understanding the background of) the best-suited diuretic regimen for the individual patient. Newer diuretic classes like vaptans and sodium glucose type 2 cotransporter inhibitors, the recent controversies on hydrochlorothiazide, and the issue of diuretic resistance, will also be briefly addressed. CONCLUSION: This educational review offers a didactical overview of diuretics in Pediatrics. WHAT IS KNOWN: • Diuretics are frequently prescribed drugs in both adults and children. • They increase water and sodium excretion, reducing fluid overload. WHAT IS NEW: • This article reviews indications, mechanisms of action, side effects, and basic pharmacokinetics facts on diuretics in Paediatrics. • It also addresses current issues, like the management of diuretic resistance, the recent controversy on hydrochlorothiazide, and the novel classes vaptans and gliflozins.

Effect of Torsemide vs Furosemide After Discharge on All-Cause Mortality in Patients Hospitalized With Heart Failure: The TRANSFORM-HF Randomized Clinical Trial.

Importance: Although furosemide is the most commonly used loop diuretic in patients with heart failure, some studies suggest a potential benefit for torsemide. Objective: To determine whether torsemide results in decreased mortality compared with furosemide among patients hospitalized for heart failure. Design, Setting, and Participants: TRANSFORM-HF was an open-label, pragmatic randomized trial that recruited 2859 participants hospitalized with heart failure (regardless of ejection fraction) at 60 hospitals in the United States. Recruitment occurred from June 2018 through March 2022, with follow-up through 30 months for death and 12 months for hospitalizations. The final date for follow-up data collection was July 2022. Interventions: Loop diuretic strategy of torsemide (n = 1431) or furosemide (n = 1428) with investigator-selected dosage. Main Outcomes and Measures: The primary outcome was all-cause mortality in a time-to-event analysis. There were 5 secondary outcomes with all-cause mortality or all-cause hospitalization and total hospitalizations assessed over 12 months being highest in the hierarchy. The prespecified primary hypothesis was that torsemide would reduce all-cause mortality by 20% compared with furosemide. Results: TRANSFORM-HF randomized 2859 participants with a median age of 65 years (IQR, 56-75), 36.9% were women, and 33.9% were Black. Over a median follow-up of 17.4 months, a total of 113 patients (53 [3.7%] in the torsemide group and 60 [4.2%] in the furosemide group) withdrew consent from the trial prior to completion. Death occurred in 373 of 1431 patients (26.1%) in the torsemide group and 374 of 1428 patients (26.2%) in the furosemide group (hazard ratio, 1.02 [95% CI, 0.89-1.18]). Over 12 months following randomization, all-cause mortality or all-cause hospitalization occurred in 677 patients (47.3%) in the torsemide group and 704 patients (49.3%) in the furosemide group (hazard ratio, 0.92 [95% CI, 0.83-1.02]). There were 940 total hospitalizations among 536 participants in the torsemide group and 987 total hospitalizations among 577 participants in the furosemide group (rate ratio, 0.94 [95% CI, 0.84-1.07]). Results were similar across prespecified subgroups, including among patients with reduced, mildly reduced, or preserved ejection fraction. Conclusions and Relevance: Among patients discharged after hospitalization for heart failure, torsemide compared with furosemide did not result in a significant difference in all-cause mortality over 12 months. However, interpretation of these findings is limited by loss to follow-up and participant crossover and nonadherence. Trial Registration: ClinicalTrials.gov Identifier: NCT03296813.

Revisiting diuretic choice in chronic kidney disease.

PURPOSE OF REVIEW: Existing guidelines offer little direction about the use of thiazide and loop diuretics in patients with chronic kidney disease (CKD). This review summarizes recent studies impacting indications and safety considerations for these agents in patients with CKD. RECENT FINDINGS: Chlorthalidone reduces blood pressure compared to placebo in patients with advanced CKD, challenging the belief that thiazide diuretics lose efficacy at lower glomerular filtration rates (GFR). Existing studies show no clear impact of thiazide or loop diuretic use on kidney or cardiovascular outcomes in patients with CKD. Sodium-glucose co-transporter type 2 (SGLT2) inhibitors have diuretic effects, but concomitant use of a diuretic does not diminish the preventive benefits of these agents against acute kidney injury (AKI). Despite theoretical concerns, thiazide diuretics likely do not worsen circulating vasopressin levels or cyst progression in polycystic kidney disease and may be useful for alleviating polyuria from tolvaptan. Diuretics cause multiple adverse effects, including electrolyte abnormalities, hemodynamic-mediated decrease in estimated GFR, and AKI. SUMMARY: Recent evidence supports expanded indications for diuretics in patients with kidney disease, including chlorthalidone for hypertension in advanced CKD. Monitoring electrolytes and estimated GFR is critical to ensure patient safety when prescribing these agents for patients with CKD.

Association of diuretic use with increased risk for long-term post-transplantation diabetes mellitus in kidney transplant recipients.

BACKGROUND: Post-transplantation diabetes mellitus (PTDM) is a major clinical problem in kidney transplant recipients (KTRs). Diuretic-induced hyperglycaemia and diabetes have been described in the general population. We aimed to investigate whether diuretics also increase PTDM risk in KTRs. METHODS: We included 486 stable outpatient KTRs (with a functioning graft ≥1 year) without diabetes from a prospective cohort study. Participants were classified as diuretic users and non-users based on their medication use verified by medical records. RESULTS: At the baseline study, 168 (35%) KTRs used a diuretic (thiazide, n = 74; loop diuretic, n = 76; others, n = 18) and 318 KTRs did not use a diuretic. After 5.2 years [interquartile range (IQR) 4.0‒5.9] of follow up, 54 (11%) KTRs developed PTDM. In Cox regression analyses, diuretic use was associated with incident PTDM, independent of age, sex, fasting plasma glucose (FPG) and haemoglobin A1c (HbA1c) {hazard ratio [HR] 3.28 [95% confidence interval (CI) 1.84-5.83]; P <0.001}. Further adjustment for potential confounders, including lifestyle, family history of cardiovascular disease, use of other medication, kidney function, transplantation-specific parameters, BMI, lipids and blood pressure did not materially change the association. Moreover, in Cox regression analyses, both thiazide and loop diuretics associated with the development of PTDM, independent of age, sex, FPG and HbA1c [HR 2.70 (95% CI 1.24-5.29); P = 0.012 and HR 5.08 (95% CI 2.49-10.34); P <0.001), respectively]. CONCLUSIONS: This study demonstrates that diuretics overall are associated with an increased risk of developing PTDM in KTRs, independent of established risk factors for PTDM development. The association was present for both thiazide and loop diuretics.

Association between gabapentinoids and oedema treated with loop diuretics: A pooled sequence symmetry analysis from the USA and Denmark.

AIMS: To assess the gabapentinoid-oedema-loop diuretic prescribing cascade in adults using large administrative health care databases from the USA and Denmark. METHODS: This study used a sequence symmetry analysis to assess loop diuretic initiation before and after the initiation of gabapentinoids among patients aged 20 years or older without heart failure or chronic kidney disease. Data from MarketScan Commercial and Medicare Supplemental Claims databases (2005 to 2019) and Danish National Prescription Register (2005 to 2018) were analyzed. Use of loop diuretics associated with initiation of selective norepinephrine reuptake inhibitors (SNRI) was used as a negative control. We assessed the pooled temporality of loop diuretic initiation relative to gabapentinoid or SNRI initiation across the 2 countries. Secular trend-adjusted sequence ratios (aSRs) with 95% confidence intervals (CIs) were calculated using data from 90 days before and after initiation of gabapentinoids. Pooled ratio of aSRs were calculated by comparing gabapentinoids to SNRIs. RESULTS: Among the 1 511 493 gabapentinoid initiators (Denmark [n = 338 941]; USA [n = 1 172 552]), 20 139 patients had a new loop diuretic prescription 90 days before or after gabapentinoid initiation, resulting in a pooled aSR of 1.33 (95% CI 1.06-1.67). The pooled aSR for the negative control (i.e., SNRI) was 0.84 (95% CI 0.75-0.94), which resulted in a pooled ratio of aSRs of 1.58 (95% CI 1.23-2.04). Pooled estimated incidence of the gabapentinoid-loop diuretic prescribing cascade was 8.14 (95% CI, 1.92-34.49) events per 1000 patient-years. CONCLUSION: We identified evidence of the gabapentinoid-oedema-loop diuretic prescribing cascade in 2 countries.

Evaluation of the key prescription sequence symmetry analysis assumption using the calcium channel blocker: Loop diuretic prescribing cascade.

OBJECTIVES: To evaluate the prescription sequence symmetry analysis assumption regarding balance between marker drug (i.e., medication used to treat a drug-induced adverse event) initiation rates before and after initiation of an index drug (i.e., medication that is potentially associated with the drug-induced adverse event) in the absence of prescribing cascades, we used a well-described example of loop diuretic initiation to treat dihydropyridine calcium channel blockers (DH CCB)-induced edema. STUDY DESIGN AND SETTING: The University of Florida Health Integrated Data Repository from June 2011 and July 2018 was used to assess temporal prescribing of DH CCB and loop diuretics within the prescription sequence symmetry analysis framework. Validation of the prescribing cascade was performed via clinical expert chart review. RESULTS: Among patients without heart failure who were initiated on DH CCB, 26 and 64 loop diuretics initiators started within 360 days before versus after DH CCB initiation, respectively, resulting in an adjusted sequence ratio (aSR) of 2.27 (95% CI, 1.44-3.58). Overall, 35 (54.7%) patients were determined to have a prescribing cascade. Removing patients who experienced a prescribing cascade resulted in an aSR of 1.05, 95% CI 0.62-1.78). CONCLUSION: Loop diuretic initiation rates before and after DH CCB initiation for reasons other a prescribing cascade were similar, thus confirming the prescription sequence symmetry analysis assumption.

Risk of volume depletion events with concomitant use of sodium glucose co-transporter 2 inhibitors and loop diuretics: A self-controlled case series study.

BACKGROUND: Sodium glucose co-transporter 2 inhibitors (SGLT2is) are used to prevent cardiovascular complications in type 2 diabetes mellitus (T2DM) and newly indicated to treat heart failure (HF). Loop diuretics are commonly prescribed to manage volume overload in HF and may increase the risk of volume depletion in real-world practice. This study evaluated the risk of volume depletion following concomitant use of SGLT2is and loop diuretics in veterans. METHODS: Veterans with T2DM were included if they received concomitant loop diuretics and SGLT2is and experienced at least one volume depletion event between December 2012 and December 2019, utilizing a self-controlled case series design. Concomitant prescribing periods were divided into focal windows of 1 to 14 days, 14 to 28 days, and greater than 28 days. Incidence rate ratios (IRR) were estimated using multivariable Poisson regressions adjusted for age and renal function. RESULTS: 3352 patients experienced at least one volume depletion event and were concomitantly prescribed SGLT2is and loop diuretics at least once. The risk of volume depletion increased in the treatment versus control windows during the 1 to 14-day window (IRR = 1.82, 95% CI 1.63-2.02) the 15-to-28-day window (IRR = 1.46, 95% CI 1.28-1.67), and the greater than 28-day window (IRR = 1.22, 95% CI 1.21-1.34). CONCLUSIONS: Concomitant prescribing of SGLT2is and loop diuretics is associated with an increased risk of volume depletion, an effect that attenuates with longer therapy durations. Prescribers need to closely monitor fluid status in patients receiving concomitant therapy, especially those with advancing age or with eGFR below 60.

Central venous pressure and the risk of diuretic-associated acute kidney injury in patients after cardiac surgery.

BACKGROUND: When prescribing diuretics in the postcardiac surgical intensive care unit (ICU), clinicians may use central venous pressure (CVP) to assess volume status and the risk of acute kidney injury (AKI). In this study, we examined how the risk of diuretic-associated AKI varied with CVP in patients undergoing cardiac surgery. METHODS: We used the Medical Information Mart for Intensive Care database to study adults admitted to the postcardiac surgical ICU at an urban, academic medical center between 2001 and 2012. We examined the odds of AKI per 1-mm Hg increase in CVP among patients receiving intravenous loop diuretics using multivariable adjusted logistic regression. We examined the risk of AKI among patients with diuretic use (vs nonuse) across tertiles of CVP using inverse probability treatment weighting. RESULTS: Among 4,164 patients receiving intravenous loop diuretics, the adjusted odds of subsequent AKI were 1.11 (95% CI 1.08-1.13) times higher per mm Hg increase in mean CVP. This association was log-linear across the entire range of CVPs observed. In the analysis of diuretic use (n = 5,396), the adjusted risk ratio for AKI with diuretic use (vs nonuse) was 1.33 (95% CI 1.21-1.47) and did not materially differ across tertile of CVP. CONCLUSIONS: Higher rather than lower CVP is an independent marker of AKI risk. The risk of AKI associated with diuretic use may not be influenced by CVP. Novel methods of assessing volume status and AKI risk are needed to guide patient selection for diuretic therapy.

Efficacy and safety of early ultrafiltration in patients with acute decompensated heart failure with volume overload: a prospective, randomized, controlled clinical trial.

BACKGROUND: Ultrafiltration decreases total body water and improves the alveolar to arterial oxygen gradient. The aims of the study were to investigate the efficacy and safety of early ultrafiltration in acute decompensated heart failure (ADHF) patients. METHODS: 100 patients with ADHF within 24 h of admission were randomly assigned into early ultrafiltration (n = 40) or torasemide plus tolvaptan (n = 60) groups. The primary outcomes were weight loss and an increase in urine output on days 4 and 8 of treatment. RESULTS: Patients who received early ultrafiltration for 3 days achieved a greater weight loss (kg) (- 2.94 ± 3.76 vs - 0.64 ± 0.91, P < 0.001) and urine increase (mL) (198.00 ± 170.70 vs 61.77 ± 4.67, P < 0.001) than the torasemide plus tolvaptan group on day 4. From days 4 to 7, patients in the early ultrafiltration group received sequential therapy of torasemide and tolvaptan. Better control of volume was reflected in a greater weight loss (- 3.72 ± 3.81 vs - 1.34 ± 1.32, P < 0.001) and urine increase (373.80 ± 120.90 vs 79.5 ± 52.35, P < 0.001), greater reduction of B-type natriuretic peptide (BNP) (pg/mL) (- 1144 ± 1435 vs - 654.02 ± 889.65, P = 0.037), NYHA (New York Heart Association) functional class (- 1.45 ± 0.50 vs - 1.17 ± 0.62, P = 0.018), jugular venous pulse (JVP) score (points) (- 1.9 ± 1.13 vs - 0.78 ± 0.69, P < 0.001), inferior vena cava (IVC) diameter (mm) (- 15.35 ± 11.03 vs - 4.98 ± 6.00, P < 0.001) and an increase in the dyspnea score (points) (4.08 ± 3.44 vs 2.77 ± 2.03, P = 0.035) in the early ultrafiltration group on day 8. No significant differences were found in the readmission and mortality rates in the 2 patient groups at the 1-month and 3-month follow-ups. Both groups had a similar stable renal profile. CONCLUSION: Early ultrafiltration is superior to diuretics for volume overload treatment initiation of ADHF patients. Trial registration Chinese Clinical Trial Registry, ChiCTR2000030696, Registered 10 March 2020-Retrospectively registered, https://www.chictr.org.cn/showproj.aspx?proj=29099 .

Evaluating the confounding effects of medical therapies on potassium intake assessment in patients with heart failure.

BACKGROUND AND AIMS: Potassium-wasting (loop diuretics [LD]) and potassium-sparing (spironolactone) medications used for heart failure (HF) may alter renal potassium handling and confound the use of twenty-four-hour (24-h) urine collections as a surrogate marker for potassium intake, an effect that has been observed with dietary sodium assessment. The objective was to determine the strength of association between 24-h urine collections and weighed food records in assessing potassium intake in HF patients stratified by LD usage and spironolactone usage. METHODS AND RESULTS: Stable outpatients with HF simultaneously completed two 24-h urine collections and two weighed food records on consecutive days. Analyses compared patients stratified by LD and/or spironolactone use. Pearson's correlation and the Bland-Altman method of agreement assessed the relationship between the techniques. Overall, 109 patients (61 ± 11 yrs, 74% male) were included. The mean difference in dietary potassium estimated between 24-h urine collections and food records was -353 ± 1043 mg (p < 0.01) for all patients, with no differences between measures among subgroups. The association between the two methods was r = 0.551 (95% CI, 0.373 to 0.852, p < 0.001) for LD users; r = 0.287 (95% CI, 0.01 to 0.570, p = 0.050) for LD non-users; r = 0.321 (95% CI, 0.13 to 0.798, p = 0.043) for spironolactone users, and; r = 0.534 (95% CI, 0.331 to 0.747, p < 0.001) for spironolactone non-users. There were no significant mean biases identified as part of the Bland-Altman analysis. CONCLUSION: Among HF patients, potassium-wasting and potassium-sparing medications do not influence the agreement between the two methods in the assessment of potassium intake.

Treatment outcomes of bumetanide continuous infusion: A systematic review and meta-analysis.

The clinical use of continuous bumetanide infusion for acute heart failure and volume overload is common. However, there is not enough supporting evidence for the use of continuous bumetanide infusion. Thus, we conducted this systematic review and meta-analysis aiming to describe the treatment outcomes of continuous bumetanide infusion. We searched Ovid MEDLINE, EMBASE and the Cochrane Library for eligible publications. Inclusion criteria were patients age ≥18 years with bumetanide infusion for heart failure, acute kidney injury (AKI) or volume overload. From 1564 citations, three studies (n = 94 patients) were included in the systematic review and meta-analysis. The mean dose of bumetanide was 1.08 ± 0.43 mg/hour with a mean treatment duration of 45.09 ± 10.12 hours. Mean urine output in response to continuous bumetanide infusion was 1.88 mL/kg/hour (95% confidence interval [CI], 1.72-2.05). The incidence of AKI with continuous bumetanide infusion was 24.7% (95% CI, 8.2-54.6). By using Pearson's correlation coefficient, increasing doses of bumetanide were correlated with increased urine output (P = .026) and increased incidence of AKI (P < .01). There was no correlation between increasing urine output and the incidence of AKI (P = .739). In conclusion, with available evidence, continuous bumetanide infusion may be used in the treatment of acute heart failure or volume overload with close monitoring for new-onset or worsening AKI.