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Background: Diuretic resistance is a relevant clinical issue in acute heart failure (AHF), but a standardized, quantitative definition is still missing. The aim of this analysis was to highlight discrepancies between previously proposed definitions of diuretic response and to propose a new urinary sodium (NaU)-based definition of diuretic efficiency (DE) to identify diuretic resistant (DR) patients., Methods: Three historical definitions of diuretic response and a new NaU-based DE definition, evaluating total NaU after the first diuretic bolus per 40 mg furosemide administered, were applied in a retrospective analysis to an AHF population treated with intravenous (i.v.) loop diuretics. Baseline characteristics, in-hospital clinical data and outcomes at discharge and mid-term follow-up were collected and compared among DR and non-DR patients for each definition., Results: Among 53 patients, 39 (73.6%), 51 (96.2%) and 3 (5.7%) were DR according to weight-derived, diuresis-derived, and spot NaU definition, respectively. The median value of the new NaU-based definition was 31 mmol/40 mg and patients were stratified accordingly. DR patients showed lower cumulative diuresis (5200 mL, 3300-6700 vs 9825 mL, 6200-12200, p = 0.007) and weight loss (4 kg, 1-5 vs 6 kg, 3-8.5, p = 0.023), higher BNP levels (808 pg/mL, 443-1037 vs 351 pg/mL, 209-859, p = 0.062) at the conclusion of protocol-guided i.v diuretic therapy, which was less frequently stopped due to decongestion in DR as compared to non-DR patients (57.7% vs 85.2%, p = 0.026). Six-months mortality or HF hospitalizations were more frequent in DR patients (OR 18.6, 95% CI 2.1-161.2, p = 0.008)., Conclusions: The NaU-based DE definition might solve discrepancies of other previously proposed definitions., Competing Interests: Declaration of competing interest The authors report no relationships that could be construed as a conflict of interest., (Copyright © 2024. Published by Elsevier B.V.)

Fluid overload predicts morbidity and mortality in dialysis patients. Diuretics can reduce fluid overload, but their effects on morbi-mortality following inception remain ill-defined. To determine whether diuretics reduce mortality and hospitalization rates in incident dialysis patients in the first 2 years after inception. Adult patients starting dialysis between 2009 and 2015 in the REIN registry were matched with the SNDS database and divided into four subgroups according to loop diuretics exposure: < 5%, 5-50%, 50-80% or > 80% over the observation period of each patient. The incidence of hospitalization was described based on the primary diagnoses of the discharge summaries and codes. In this study, which included 67,736 patients, 53,829 (79.5%) who had varying degrees of diuretic exposure exhibited a significantly lower mortality rate at 2 years compared to those without diuretic exposure (24.8% [95% CI 24.4-25.2], vs 37.5% [95% CI 36.7-38.3] respectively). However, the duration of diuretic exposure significantly impacted outcomes. The all-cause mortality rate at two years was highest in the group with ≥ 80% exposure (68.2% [95% CI 67.3-69.1]), followed by those with 50-80% exposure (15.7% [95% CI 15.0-16.4]), and those with 5-50% exposure (6.6% [95% CI 6.3-7.0]). An inverse probability weighting (IPW) propensity score analysis supported these findings. Stratified analyses showed consistent results regardless of a history of congestive heart failure and were similar for both hemodialysis and peritoneal dialysis patients. Additionally, the number of hospitalizations and length of stay were generally higher in the group with the longest exposure to loop diuretics. Diuretic exposure was generally associated with a lower mortality rate in dialysis patients. However, prolonged exposure (≥ 80%) was linked to an increased risk of mortality and hospitalization. This prolonged exposure may indicate residual diuresis at the cost of chronic fluid overload., Competing Interests: Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Background: Patient medication knowledge and health literacy affect patient safety. Taking angiotensin-converting enzyme inhibitors (ACE-i) or angiotensin II receptor blockers (ARBs), with diuretics and non-steroidal anti-inflammatory medications (NSAIDs) is nephrotoxic. Patients may not know of this risk. An eHealth information package was developed to inform patients at risk of taking this combination of medication., Objective: To assess the impact of the eHealth information package on patient knowledge and behaviour., Design: This was a two-arm, parallel, randomised control trial. A knowledge quiz and NSAID use survey were undertaken at baseline, and repeated after two weeks. The intervention group accessed the information package after completing the baseline assessment. The control group received normal care., Setting and Participants: Primary healthcare patients prescribed an ACE-i or ARB plus a diuretic in Aotearoa New Zealand., Intervention: A novel eHealth information package was made available to participants in the intervention group consisting of a downloadable PDF and online education activity. This took approximately 15 min for participants to complete., Primary Outcome Measures: Change in knowledge scores and in NSAID use between pre-intervention and post-intervention assessment., Secondary Outcome Measures: Self-reported patient intentions regarding future NSAID use RESULTS: The 201 participants who completed the study had high baseline NSAID medication knowledge, which did not substantially change at follow-up. The intervention group had a 0.35 (95% CI: -0.18, 0.88) higher knowledge score than the control group. NSAID use decreased over the study; the intervention group had 62% lower odds of NSAID use at follow-up assessment compared with the control group (OR=0.37, 95% CI: 0.14, 1.03). There was no substantial difference between study groups at follow-up for self-reported action. The information package was considered acceptable and useful., Conclusion: This tailored eHealth information package may reduce NSAID use in patients at increased risk from NSAID-related harm., Trial Registration Number: Australian New Zealand Clinical Trial Registry (ACTRN:12622001132730)., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Fluid assessment and management is a key aspect of good dialysis care and is affected by patient-level characteristics and potentially centre-level practices. In this secondary analysis of the BISTRO trial we wished to establish whether centre-level practices with the potential to affect fluid status were stable over the course of the trial and explore if they had any residual associations with participant's fluid status., Methods: Two surveys (S) of fluid management practices were conducted in 32 participating centres during the trial, (S1: 2017-18 and S2: 2021-22). Domains interrogated included: dialysate sodium concentration, (D-[Na + ]), fluid and salt intake, residual kidney function, use of diuretics, incremental start, approaches to fluid assessment, management and dialysate temperature, (D- o C). Associations of these practices with the closeness of the participant's post-dialysis target weight to their normally hydrated weight, pre- and post-dialysis systolic (SBP) and diastolic blood pressure, (DBP), were analysed using intra-class correlations and multilevel modelling with adjustment for visit, age, sex and comorbidity burden., Results: Variations in centre practices were reported but did not change during the trial, apart from some relaxation in salt and fluid restriction in S2. For our measures of fluid status, measured 2501 times in 439 non-anuric incident haemodialysis patients, centre-level intraclass correlations were extremely low, whereas patient-level correlations ranged between 0.12 and 0.47, strongest for pre- and post-dialysis-SBP, less so for post-dialysis-DBP. Multi-level analysis found no associations between D-[Na + ], or assessment methods of fluid status. In S2, one centre, routinely using a D-C o of 35°C had more divergence between the target and normally hydrated weight, but this was not observed in S1, and no other associations were found., Conclusions: Centre-level fluid management practices were stable over the course of the BISTRO trial, and in contrast to patient-level factors, no centre-level associations were detected with fluid status or blood pressure. This may be because the trial imposed a standardised approach to fluid assessment in all trial participants who at least initially had residual kidney function, potentially over-riding the effects of other centre practices. Survey responses revealed substantial scope for developing and evaluating standardised protocols to optimise fluid management., (© 2024. The Author(s).)

Background: Electrolyte abnormalities (EAs) worsen the clinical course of patients with heart failure (HF). The patterns of EAs vary among patients with HF. This study investigated patterns and factors associated with EAs among patients with HF admitted to Hoima Regional Referral Hospital (HRRH) in western Uganda., Methods: This hospital-based cross-sectional study used quantitative data of 384 HF patients admitted at HRRH between 21st February and 15th May 2023. Data on sociodemographic, lifestyle, and medical characteristics were collected and presented as descriptive statistics. EAs were considered electrolyte values below or above the reference normal ranges. Bivariate and multiple logistic regression analyses were conducted to establish associations. An association with a p < 0.05 is considered statistically significant., Results: Of 384 HF patients, 342 (89.1%) had EAs. Hypocalcemia was the most common EA, 165 (43.0%). Among the patients, 69 (18.0%) were on diuretics, 185 (48.2%) were on angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin receptor blockers (ARBs), and 105 (27.3%) were on calcium channel blockers (CCBs). Additionally, 264 (68.8%) had a history of hypertension, and 20 (5.2%) demonstrated good drug adherence. Patients with good drug adherence had lower odds of EAs (Adjusted Prevalence Odds Ratio [Adjusted POR] = 0.2, 95% CI: 0.1-0.7, p = 0.009). Those on diuretics had higher odds of EAs compared to those on ACEIs/ARBs and CCBs, with an Adjusted POR of 5.7 (95% CI: 1.3-15.0, p = 0.019). A history of hypertension also increased the odds of EAs (Adjusted POR = 4.0, 95% CI: 1.9-8.4, p < 0.001)., Conclusions: The prevalence of EAs in patients with HF at HRRH was high, with hypocalcemia being the most common. Patients with good drug adherence had lower odds of EAs. On the other hand, diuretic use and a history of hypertension were associated with increased odds of EAs., (© 2024. The Author(s).)

Background: One-third of patients with acute decompensated heart failure (ADHF) develop worsening kidney function, known as type I cardiorenal syndrome (CRS). CRS is linked to higher mortality rates, prolonged hospital stays, and increased readmissions., Objectives: To explore the impact of real-time monitoring of urinary output (UO) trends on personalized pharmacologic management, fluid balance, and clinical outcomes of patients with ADHF admitted to a cardiac intensive care unit., Methods: Our study comprised 35 patients who were hospitalized with ADHF and continuously monitored for UO (UOelec). Standard diuretic and fluid protocols were implemented after 2 hours of oliguria, and patient outcomes were compared to a historical matched control (HMC) group. Patients were assessed for daily and cumulative fluid balance (over 72 hours) as well as for the occurrence of acute kidney injury (AKI)., Results: Significantly more patients in the UOelec group demonstrated negative fluid balance daily and cumulatively over time in the intensive care unit compared to the HMC group: 91% vs. 20%, respectively (P < 0.0001 for 72-hour cumulative fluid balance). The incidence of AKI was significantly lower in the UOelec monitoring cohort compared to the HMC: 23% vs. 57%, respectively (P = 0.003). Moreover, higher AKI resolution, and lower peak serum creatinine levels were demonstrated in the UOelec group vs. the HMC group., Conclusions: Implementing real-time monitoring of UO in ADHF patients allowed for early response to oliguria and goal-directed adjustment to treatment. This finding ultimately led to reduced congestion and contributed to early resolution of AKI.

Heart failure is a common condition in the older population. As severity progresses, fluid accumulates resulting in congestive symptoms. Loop diuretics are the cornerstone of managing fluid overload and dosing should target euvolemia and congestive symptoms. Volume status is difficult to assess but signs and symptoms such as dyspnea, orthopnea, edema, and weight changes can be evaluated even without specialized equipment in the outpatient setting. Pharmacists are capable of assessing diuretic response and making recommendations for dosing changes in older heart failure patients.

Background: Acute decompensated heart failure (ADHF) patients with symptomatic congestion often require in-hospital admission for intravenous (IV) diuretic, impacting both patient well-being and healthcare expenses. Subcutaneous (SC) furosemide has a potential to facilitate outpatient management of ADHF patients. Thus, this study aims to assess the efficacy and safety of SC furosemide utilization, offering a potential alternative to traditional IV administration., Methods: A systematic search was conducted until April 14 2024 across scientific databases. This review included studies comparing SC furosemide with oral and IV formulations in adult HF patients., Results: This study analyzed 687 patients from 20 studies. The results demonstrate that SC furosemide can effectively manage symptomatic congestion in HF patients and results in significant cost reductions, symptom relief, and improved quality of life. Although further investigation into mortality rates is needed, SC furosemide demonstrates efficacy comparable to IV furosemide in diuresis and weight loss, with similar bioavailability and natriuretic effects. Adverse events are generally minor, predominantly related to skin irritation. Innovative strategies, such as developing isotonic alkaline solutions and improved infusion devices, are being explored to address these challenges., Conclusion: SC furosemide offers a promising alternative for managing ADHF, particularly in symptomatic HF patients with volume overload. The integration of SC furosemide into routine clinical practice and future guidelines, could optimize the management of HF, reducing hospital admission and improving patient outcomes., (© 2024. The Author(s).)

Objective: This study investigated whether serum uric acid levels are more elevated in the aspirin-ticagrelor group than in the aspirin-clopidogrel group. Materials and Materials and methods: We conducted a retrospective cohort study with patients between 2013 and 2020. Baseline and maximum serum uric acid levels within a 6-month follow-up period were analyzed to determine the increase in both groups., Results: A total of 41,877 patients were enrolled. A statistically significant elevation of serum uric acid levels was found in the aspirin-ticagrelor group compared to the aspirin-clopidogrel group (odds ratio (OR; 95% confidence interval (CI)) = 1.36 (1.15 - 1.60), p < 0.001). Kidney dysfunction and diuretic use were also identified as risk factors for uric acid elevation., Conclusion: Monitoring serum uric acid levels is recommended during aspirin-ticagrelor therapy, especially in patients with kidney dysfunction or those using diuretics.

Background: Therapies are needed to address worsening congestion, without hospitalization, in patients with chronic heart failure (HF)., Objectives: This pilot study assessed outcomes of a novel subcutaneous (SC) furosemide formulation compared to usual care in outpatients with worsening congestion., Methods: Participants with chronic HF and worsening congestion were randomized open-label 2:1 to SC furosemide compared to usual care (UC). Decongestion was estimated by tracking body weight. The primary endpoint was a win ratio of a 30-day hierarchical composite of cardiovascular death, HF events, and change in N-terminal pro-B-type natriuretic peptide. Secondary endpoints included dyspnea severity, functional capacity, and quality of life., Results: Thirty-four participants were randomized to SC furosemide and 17 to UC. SC furosemide caused greater reduction in body weight: between-group difference in least square mean change was -2.02 kg at day 3 (95% CI: -3.9 to -0.14; P = 0.035). SC furosemide-to-UC win ratio was 1.11 (95% CI: 0.48-2.50; P = 0.806). Significant between-group least square mean differences favoring SC furosemide occurred in 7-point dyspnea score (P = 0.017) and 6-minute walk test (P = 0.032), with trend in Kansas City Cardiomyopathy Questionnaire (KCCQ)-12 Overall Summary Score of 9.15 (95% CI: 1.95-20.3; P = 0.106). The most common related adverse event with SC furosemide was mild infusion site pain (11.8%)., Conclusions: SC furosemide augmented weight loss in patients with HF and worsening congestion. The composite primary endpoint was not statistically significant in this pilot investigation. However, findings of improved dyspnea scores and functional capacity, with favorable trend in KCCQ-12 score, warrant additional investigation to further document the clinical value of SC furosemide as an alternative to hospitalization (AT HOME-HF [Avoiding Treatment in the Hospital With Furoscix for the Management of Congestion in Heart Failure-A Pilot Study]; NCT04593823)., Competing Interests: Funding Support and Author Disclosures This study was funded by scPharmaceuticals, Inc. Dr M.A. Konstam has received personal fees from Alnylam, Boehringer-Ingelheim, Cardurian, LivaNova, scPharmaceuticals, Fire 1, Vicardia, and Alleviant. Dr Dhingra has received personal fees from scPharmaceuticals, Bristol Myers Squibb, and CareDx. Dr Walsh has received personal fees from scPharmaceuticals. Ms Ordway has received personal fees from scPharmaceuticals. Dr Pursley has received personal fees from scPharmaceuticals. Dr McLean has received personal fees from scPharmaceuticals. Mr Saha is a full-time employee of Cardiovascular Clinical Science Foundation. Dr Close is a full-time employee of EmpiriStat, Inc. Mr J.M. Konstam is a full-time employee of iQVIA. Dr Luepke is a full-time employee of scPharmaceuticals. Dr Mohr is a full-time employee of scPharmaceuticals. Dr Udelson has received personal fees from scPharmaceuticals, Merck, Alleviant, Reprieve CV, and Cardurion., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

None of the spironolactone trials in heart failure (HF) assessed the blood pressure (BP) responses to exercise, while conflicting results were reported for exercise capacity. In the HOMAGE trial, 527 patients at increased HF risk were randomized to usual treatment with or without spironolactone (25-50 mg/day). The current substudy included 113 controls and 114 patients assigned spironolactone, who all completed the incremental shuttle walk test at baseline and months 1 and 9. Quality of life (QoL) was assessed by EQ5D questionnaire. Between-group differences (spironolactone minus control [Δs]) were analyzed by repeated measures ANOVA with adjustment for baseline and, if appropriate, additionally for sex, age and body mass index. Δs in the pre-exercise systolic/diastolic BP were -8.00 mm Hg (95% CI, -11.6 to -4.43)/-0.85 mm Hg (-2.96 to 1.26) at month 1 and -9.58 mm Hg (-14.0 to -5.19)/-3.84 mm Hg (-6.22 to -1.47) at month 9. Δs in the post-exercise systolic/diastolic BP were -8.08 mm Hg (-14.2 to -2.01)/-2.07 mm Hg (-5.79 to 1.65) and -13.3 mm Hg (-19.9 to -6.75)/-4.62 mm Hg (-8.07 to -1.17), respectively. For completed shuttles, Δs at months 1 and 9 were 2.15 (-0.10 to 4.40) and 2.49 (-0.79 to 5.67), respectively. Δs in QoL were not significant. The correlations between the exercise-induced BP increases and the number of completed shuttles were similar in both groups. In conclusion, in patients at increased risk of developing HF, spironolactone reduced the pre- and post-exercise BP, but did not improve exercise capacity or QoL., (© 2024. The Author(s).)

Diuresis to achieve decongestion is a central aim of therapy in patients hospitalized for acute decompensated heart failure (ADHF). While multiple approaches have been tried to achieve adequate decongestion rapidly while minimizing adverse effects, no single diuretic strategy has shown superiority, and there is a paucity of data and guidelines to utilize in making these decisions. Observational cohort studies have shown associations between urine sodium excretion and outcomes after hospitalization for ADHF. Urine chemistries (urine sodium ± urine creatinine) may guide diuretic titration during ADHF, and multiple randomized clinical trials have been designed to compare a strategy of urine chemistry-guided diuresis to usual care. This review will summarize current literature for diuretic monitoring and titration strategies, outline evidence gaps, and describe the recently completed and ongoing clinical trials to address these gaps in patients with ADHF with a particular focus on the utility of urine sodium-guided strategies., (© 2024. The Author(s).)

Clinical congestion remains a major cause of hospitalization and re-hospitalizations in patients with chronic heart failure (HF). Despite the high prevalence of this issue and clinical concern in HF practice, there is limited understanding of the complex pathophysiology relating to the "congestion" of congestive HF. There is no unifying definition or clear consensus on what is meant or implied by the term "congestion." Further, the discordance in study findings relating congestion to physical signs and symptoms of HF, cardiac hemodynamics, or metrics of weight change or fluid loss with diuretic therapy has not added clarity. In this review, these factors will be discussed to add perspective to this issue and consider the factors driving "congestion." There remains a need to better understand the roles of fluid retention promoting intravascular and interstitial compartment expansions, blood volume redistribution from venous reservoirs, altered venous structure and capacity, elevated cardiac filling pressure hemodynamics, and heterogeneous intravascular volume profiles (plasma volume and red blood cell mass) with a goal to help demystify "congestion" in HF. Further, this includes highlighting the importance of recognizing that congestion is not the result of a single pathway but a complex of responses some of which produce symptoms while others do not; yet, we confine these varied responses to the single and somewhat vague term "congestion.", (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Idiopathic edema (IE) is a disease that occurs predominantly in women. It is characterized by increasing weight gain of >1.4 kg from morning to night, increasing edema, increasing truncal and abdominal girth with bloating when assuming an upright position and nocturia that is unrelated to menses. There is an increase in morbidity but not mortality. Increased capillary membrane leakage appears to be the underlying pathophysiologic abnormality that explains the myriad of clinical presentations. We present 2 cases of life-threatening complications of IE that resulted in seizures related to acute hyponatremia in one and extreme postural dizziness and fainting induced by postural hypotension in the other. The first patient was successfully treated with salt restriction, timely use of furosemide and limitation of water intake; the other was successfully treated by use of support hose. Treatment of these patients required a fundamental understanding of the intricate pathophysiological consequences of a leaky capillary membrane, an understanding of Starling forces and detailing the effectiveness of a low salt diet, use of diuretics and limited water intake in one and why support hose would be beneficial in the other patient. Both patients experienced significant physical and emotional benefits that substantially improved quality of life., Competing Interests: Conflicts of interest The authors whose names are listed immediately below certify that they have NO affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants; participation in speakers’ bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements), or non-financial interest (such as personal or professional relationships, affiliations, knowledge or beliefs) in the subject matter or materials discussed in this manuscript., (Copyright © 2024 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved.)

Objectives: Antihypertensives reduce the risk of myocardial infarction and stroke. Restrictions during the COVID-19 pandemic limited access to healthcare, which may have had a negative impact on drug prescribing. This study aimed to assess the effect of the COVID-19 pandemic on the initiation of antihypertensive drugs., Design: Interrupted time series study using a segmented linear regression model., Setting: Swedish population assessed through linked national healthcare registers., Participants: 720 300 new users of antihypertensives., Intervention: March 2020, COVID-19 pandemic onset., Main Outcomes Measures: The change in the initiation of antihypertensives expressed as monthly cumulative incidence, stratified by age and sex. Data on dispensed prescriptions of diuretics, beta-blockers, calcium channel blockers, ACE inhibitors (ACEi) and angiotensin receptor blockers were extracted from the Swedish Prescribed Drug Register, from March 2018 to November 2021. Initiation (new use) was defined as having no previous dispensations before March 2019. Monthly cumulative incidence in March 2019-November 2021 was calculated as the number of patients initiating each drug class in each month divided by the population., Results: The start of the pandemic was associated with an immediate drop in the initiation of any antihypertensive, but no sustained effects were observed, as the incidence continued to increase in the postinterruption period by +0.02% each month in both sexes. The immediate drop was statistically significant for ACEi in both sexes and all antihypertensive classes except diuretics in patients >65 years. А significant postintervention trend change was observed for initiation of diuretics (+0.013% overall), driven mainly by a significant increase in patients >65 years. Similar findings were also observed for diuretics in females (+0.02%) and ACEi (+0.03%) in patients >65 years., Conclusions: The pandemic had an immediate negative short-term effect, but we found no major long-term negative influence of the COVID-19 pandemic on initiation of any type of antihypertensive drugs., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Background: Heart failure is a clinical syndrome characterized by decreased cardiac output, leading to systemic organ hypoxia and resulting in dyspnea, pulmonary edema, organ congestion, and pleural effusion. Owing to the diverse clinical manifestations of heart failure, early diagnosis can be challenging, and misdiagnosis may occur occasionally. The use of echocardiography and blood brain natriuretic peptide can aid in obtaining a more accurate diagnosis., Case Presentation: This article presents two case reports of patients who were misdiagnosed with acute cholecystitis. Both patients were young Mongolia males (age 26 and 39 years) who presented to the emergency department with acute upper abdominal pain, abdominal ultrasound revealed gallbladder enlargement, and blood tests suggested mild elevation of bilirubin levels. However, despite the absence of procalcitonin and C-reactive protein elevation, the patients were admitted to the general surgical department with a diagnosis of "acute cholecystitis." Both patients were given treatment for cholecystitis, but their vital signs did not improve, while later examinations confirmed heart failure. After treatment with diuretics and cardiac glycosides, both patients' symptoms were relieved., Conclusion: We aim to highlight the clinical manifestations of heart failure and differentiate it from rare conditions such as acute cholecystitis. Physicians should make accurate diagnoses on the basis of physical examinations, laboratory testing and imaging, and surveys while avoiding diagnostic heuristics or mindsets. By sharing these two case reports, we hope to increase awareness to prevent potential complications and improve patient outcomes., (© 2024. The Author(s).)

Background: Diagnostic variables from insertable cardiac monitors may be useful in identifying patients at increased risk of heart failure (HF) events. High-risk alerts must be coupled with interventions to improve outcomes. We aim to assess the safety of a predefined protocolized intervention pathway activated by insertable cardiac monitor high-risk alerts., Methods and Results: ALLEVIATE-HF (Algorithm Using LINQ Sensors for Evaluation and Treatment of Heart Failure) Phase 1 was a randomized interventional study enrolling patients with New York Heart Association class II/III and a recent HF event. A HF risk score based on insertable cardiac monitor diagnostics, including impedance, respiration rate, atrial fibrillation burden, heart rate during atrial fibrillation, heart rate variability, and activity duration, was calculated. A protocolized intervention pathway was activated when high-risk scores were detected that involved physician-prescribed nurse-implemented uptitration of diuretic for 4 days, unless safety rule-out conditions were met. Interventions could be repeated if high-risk scores persisted and did not require worsening symptoms. In total, 59 patients were randomized (mean age 68.2±11.8 years; 59.3% male); 67.8% with ejection fraction ≥50%. The mean follow-up was 11.8±8.1 months. Overall, 146 high-risk scores were recorded in 33 patients and 118 interventions occurred in 75 (51.4%) high-risk alerts that did not meet safety rule-out criteria. There were no serious adverse events and 13 adverse events related to interventions. In patients with symptoms at intervention initiation, symptoms resolved in 37 interventions (80%) and worsened in 8 (17%). In asymptomatic patients, symptoms developed in 3 interventions (7%)., Conclusions: A personalized medication intervention based on insertable cardiac monitor risk score can be safely instituted in patients with HF, irrespective of symptoms., Registration: URL: https://www.clinicaltrials.gov; Unique Identifier: NCT04452149.

The recent guidelines issued by the European Society of Hypertension reaffirmed that the degree of control of hypertension remains suboptimal worldwide. In order to increase the proportion of well-controlled patients, in addition to nonpharmacological measures, it is necessary to improve the implementation of drug therapy in the clinical practice as much as possible. Initial therapy should almost always be based on the combination, free or fixed, between ACE inhibitor drugs, or direct angiotensin II inhibitors ('sartans') and diuretics (thiazide or thiazide-like) or calcium channel blockers at the maximum recommended and well-tolerated dose. The combination of the thiazide-like diuretic indapamide with the ACE inhibitor delapril has shown, based on numerous clinical trials and meta-analyses, very good results in terms of antihypertensive efficacy, tolerability, and prevention or regression of organ damage. Indapamide is a thiazide-like diuretic also endowed with direct vasodilator effect and long duration of action. A meta-analysis of 19 randomized clinical trials demonstrated a greater reduction in the incidence of cardiac events, stroke and heart failure with thiazide-like diuretics than with thiazide diuretics. Delapril is a non-sulfhydryl ACE-inhibitor with high affinity for converting enzyme at the cardiac, pulmonary, and peripheral vascular levels. Being strongly lipophilic, delapril inhibits the ACE enzyme at the tissue level more potently than other ACE inhibitors. A peculiar feature of delapril is its weak bradykinin-enhancing effect due to its higher affinity for the C site than the N site of ACE, resulting in a lower incidence of cough and angioneurotic edema compared with other ACE inhibitors. In some meta-analyses, the pressor reduction was statistically, greater with the delapril-indapamide combination than with combinations between hydrochlorothiazide and ACE inhibitors. The combination consists of divisible tablets containing 30 mg delapril and 2.5 mg indapamide, and its pharmacological and clinical properties are not affected by simultaneous food intake. The antihypertensive efficacy of the combination, as well as its components, persists for the entire 24 hours. The recent alarming reports on the incidence of skin cancer during treatment with hydrochlorothiazide should also be a guide in clinical practice toward the preferential choice of a thiazide-like diuretic such as chlorthalidone or indapamide to replace hydrochlorothiazide.

Aims: Combination of hypertonic saline solution (HSS) with intravenous loop diuretics has been suggested to improve diuretic response in patients hospitalized for heart failure (HF). The efficacy and safety of this approach in the ambulatory setting remain unexplored., Methods and Results: In this multicentre, double-blind, randomized study, we allocated ambulatory patients with worsening heart failure (WHF) to a 1-h infusion of intravenous furosemide ( iv Furosemide)-HSS versus iv Furosemide. The primary endpoint was the volume of diuresis at 3 h. Secondary endpoints included 3-h natriuresis and weight variation, 7-day congestion data, kidney function and electrolytes, and 30-day clinical events. Overall, 167 participants (median age: 81 years, 30.5% female) were randomized across 13 sites between December 2020 and March 2023. There were no differences in 3-h diuresis between treatments ( iv Furosemide-HSS: 1099 ml vs. iv Furosemide: 1103 ml, p = 0.963), 3-h natriuresis (∆ +2.642 mEq/L, p = 0.559), or 3-h weight (∆ +0.012 kg, p = 0.920). Patients in the iv Furosemide-HSS arm experienced significant weight decrease at 7 days (Δ -0.586 kg, p = 0.048). There were no between-treatment differences in clinical congestion score, biomarkers, inferior vena cava diameter, or the presence of lung ultrasound B-lines. At 30 days, 26.5% of the patients in the iv Furosemide-HSS group versus 33.3% in the iv Furosemide group experienced WHF (hazard ratio 0.76, p = 0.330). The incidence of death from any cause or HF hospitalization was 6% of patients in the iv Furosemide-HSS group and 8.3% of patients in the iv Furosemide group (hazard ratio 0.69, p = 0.521). The incidence of worsening kidney function or metabolic derangements was not significantly different in the two arms., Conclusions: A single infusion of iv Furosemide-HSS did not improve 3-h diuresis or congestion parameters in patients with ambulatory WHF. This therapy showed an appropriate safety profile., (© 2024 European Society of Cardiology.)

Aims: Early evaluation of the natriuretic response is recommended to guide diuretic therapy in acute decompensated heart failure (ADHF). However, its implementation in daily practice is hampered by implementation barriers and increased time constraints. The Readily Available Urinary Sodium Analysis in Patients with Acute Decompensated Heart Failure (EASY-HF) study assessed the feasibility, efficacy and safety of a nurse-led urinary sodium-based diuretic titration protocol with the use of a point-of-care urinary sodium sensor., Methods and Results: The EASY-HF study was a single-centre, randomized, open-label study comparing diuretic management at the treating physician's discretion as standard of care (SOC) with a nurse-led natriuresis-guided protocol in patients with ADHF. The LAQUAtwin Sodium Meter (HORIBA) was used as point-of-care sensor to measure urine sodium concentration. The primary endpoint was natriuresis after 48 h. Secondary endpoints included safety profile and user-friendliness of both the protocol and the point-of-care sensor. Sixty patients were randomized towards SOC (n = 30) versus protocolized care (n = 30). The mean age was 80 ± 8 years, 25% were women and median N-terminal pro-B-type natriuretic peptide was 4667 (2667-7709) ng/L. Natriuresis after 48 h was significantly higher in the protocolized versus SOC group (820 ± 279 vs. 657 ± 273 mmol; p = 0.027). Pre-defined safety endpoints were similar among both groups. The sensor-based protocol was evaluated as easy to use by the nursing staff, and preferred over urinary collections., Conclusion: A nurse-led diuretic titration protocol via a point-of-care urinary sodium sensor was feasible, safe and resulted in an increased natriuresis in ADHF compared to SOC., (© 2024 European Society of Cardiology.)

Background: The addition of hydrochlorothiazide (HCTZ) to furosemide in the CLOROTIC (Combining Loop with Thiazide Diuretics for Decompensated Heart Failure) trial improved the diuretic response in patients with acute heart failure (AHF)., Objectives: This work aimed to evaluate if these results differ across the spectrum of left ventricular ejection fraction (LVEF)., Methods: This post hoc analysis of the randomized, double-blind, placebo-controlled CLOROTIC trial enrolled 230 patients with AHF to receive either HCTZ or a placebo in addition to an intravenous furosemide regimen. The influence of LVEF on primary and secondary outcomes was evaluated., Results: The median LVEF was 55%: 166 (72%) patients had LVEF >40%, and 64 (28%) had LVEF ≤40%. Patients with a lower LVEF were younger, more likely to be male, had a higher prevalence of ischemic heart disease, and had higher natriuretic peptide levels. The addition of HCTZ to furosemide was associated with the greatest weight loss at 72 of 96 hours, better metrics of diuretic response, and greater 24-hour diuresis compared with placebo, with no significant differences according to the LVEF category (using 2 LVEF cutoff points: 40% and 50%) or LVEF as a continuous variable (all P values were insignificant). There were no significant differences observed with the addition of HCTZ in terms of mortality, rehospitalizations, or safety endpoints (impaired renal function, hyponatremia, and hypokalemia) among the 2 LVEF groups (all P values were insignificant)., Conclusions: Adding HCTZ to intravenous furosemide seems to be effective strategy for improving diuretic response in AHF without treatment effect modification according to baseline LVEF. (Combining Loop with Thiazide Diuretics for Decompensated Heart Failure [CLOROTIC], NCT01647932; Randomized, double blinded, multicenter study, to asses Safety and Efficacy of the Combination of Loop With Thiazide-type Diuretics vs Loop diuretics with placebo in Patients With Decompensated, EudraCT Number 2013-001852-36)., Competing Interests: Funding Support and Author Disclosures This work was supported by the Heart Failure Working Group of the Spanish Society of Internal Medicine. The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Congestion is a common cause of clinical deterioration and the most common clinical presentation at admission in acute heart failure (HF). Therefore, finding effective and sustainable ways to alleviate congestion has become a crucial goal for treating HF patients. Congestion is a result of complex underlying pathophysiology; therefore, it is not a direct cause of the disease but its consequence. Any therapy that directly promotes sodium/water removal only, thus targeting only clinical symptoms, neither modifies the natural course of the disease nor improves prognosis. This review aims to provide a comprehensive evaluation of the current decongestive therapies and propose a new (not diuretic-centred) paradigm of long-term congestion management in HF that attempts to correct the underlying pathophysiology, thus improving congestion, preventing its development, and favourably altering the natural course of the disease rather than merely treating its symptoms., (© 2024 The Author(s). European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: UMOD (uromodulin) has been linked to hypertension through potential activation of Na + -K + -2Cl - cotransporter (NKCC2), a target of loop diuretics. We posited that hypertensive patients carrying the rs13333226-AA UMOD genotype would demonstrate greater blood pressure responses to loop diuretics, potentially mediated by this UMOD/NKCC2 interaction., Methods: This prospective, multicenter, genotype-blinded trial evaluated torasemide (torsemide) efficacy on systolic blood pressure (SBP) reduction over 16 weeks in nondiabetic, hypertensive participants uncontrolled on ≥1 nondiuretic antihypertensive for >3 months. The primary end point was the change in 24-hour ambulatory SBP (ABPM SBP) and SBP response trajectories between baseline and 16 weeks by genotype (AA versus AG/GG) due to nonrandomized groups at baseline (ClinicalTrials.gov: NCT03354897)., Results: Of 251 enrolled participants, 222 received torasemide and 174 demonstrated satisfactory treatment adherence and had genotype data. The study participants were middle-aged (59±11 years), predominantly male (62%), obese (body mass index, 32±7 kg/m 2 ), with normal eGFR (92±17 mL/min/1.73 m²) and an average baseline ABPM of 138/81 mm Hg. Significant reductions in mean ABPM SBP were observed in both groups after 16 weeks (AA, -6.57 mm Hg [95% CI, -8.44 to -4.69]; P <0.0001; AG/GG, -3.22 [95% CI, -5.93 to -0.51]; P =0.021). The change in mean ABPM SBP (baseline to 16 weeks) showed a difference of -3.35 mm Hg ([95% CI, -6.64 to -0.05]; P =0.048) AA versus AG/GG genotypes. The AG/GG group displayed a rebound in SBP from 8 weeks, differing from the consistent decrease in the AA group ( P =0.004 for difference in trajectories)., Conclusions: Our results confirm a plausible interaction between UMOD and NKCC2 and suggest a potential role for genotype-guided use of loop diuretics in hypertension management., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03354897., Competing Interests: I.S. Mackenzie is a member of the British Heart Foundation Clinical Studies Committee. The other authors report no conflicts.

Purpose of Review: Pulmonary hypertension (PH) is commonly observed in premature infants with bronchopulmonary dysplasia (BPD) and is associated with poor outcomes and increased mortality. This review explores the management of this intricate condition of the pulmonary vasculature, which exhibits heterogeneous effects and may involve both arterial and postcapillary components., Recent Findings: Current management of BPD-PH should focus on optimizing ventilatory support, which involves treatment of underlying lung disease, transitioning to a chronic phase ventilation strategy and evaluation of the airway. Data on management is limited to observational studies. Diuretics are considered a part of the initial management, particularly in infants with right ventricular dilation. In many cases, pulmonary vasodilator therapy is required to induce pulmonary arterial vasodilation, reduce right ventricular strain, and prevent coronary ischemia and heart failure. Echocardiography plays a pivotal role in guiding treatment decisions and monitoring disease progression., Summary: BPD-PH confers a heightened risk of mortality and long-term cardio-respiratory adverse outcomes. Echocardiography has been advocated for screening, while catheterization allows for confirmation in select more complex cases. Successful management of BPD-PH requires a multidisciplinary approach, focusing on optimizing BPD treatment and addressing underlying pathologies., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Decongestion is a cornerstone therapeutic goal for those presenting with decompensated heart failure. Current approaches to clinical decongestion include reducing cardiac preload, which is typically limited to diuretics and hemofiltration. Several new technologies designed to mechanically reduce cardiac preload are in development. In this review, we discuss the pathophysiology of decompensated heart failure; the central role of targeting cardiac preload; emerging mechanical preload reduction technologies; and potential application of these devices., Competing Interests: Disclosure: N.K.K. has received consulting honoraria and institutional grant support from Abbott Laboratories, Abiomed Inc., Boston Scientific, Medtronic, LivaNova, Getinge, and Zoll. M.K.K. has served on the advisory board for Abiomed Inc., Abbott Laboratories, and CorWave. D.B. has received an unrestricted, educational grant from Abiomed Inc. A.B. is a consultant to Abiomed Inc. The other authors have no conflicts of interest to report., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the ASAIO.)

Aims: We aim to identify the most accurate marker for early prediction of poor diuretic response in acute heart failure (AHF) patients with signs of congestion requiring intravenous diuretic treatment., Methods: In this single-centre, prospective observational study, AHF patients with signs of congestion received a standardized intravenous furosemide dose (1 mg/kg of body weight; 40 mg in bolus and remaining dose in 2 h continuous infusion). Subsequently, we assessed spot urine composition at 2 h post-administration, comparing it with total urine output at 6 h. Various potential urine markers were analysed for predicting urine output using receiver operating characteristic (ROC) curves and logistic regression models. We investigated guideline-recommended markers, including spot urine sodium (UNa + ) and its cut-off, and introduced the UNa + /UCr (urine creatinine concentration) ratio adjusting UNa + for urine dilution., Results: Out of 111 patients (85% males, 66.4 ± 13.9 years old, NTproBNP 7290 [4493-14 582] pg/ml), there were 18 (16%) with a poor diuretic response (cumulative urine output <600 ml during the first 6 h). The mean 6 h cumulative diuresis in patients with poor and good diuretic response was 406 ± 142 and 2114 ± 1164 ml, respectively, P < 0.005. After an initial evaluation of several potential biomarkers, only UNa + , UCr and UNa + /UCr were selected as candidates with the highest predictive value. The cut-off for UNa + adjusted for urine dilution: UNa + /UCr ratio <0.167 mmol/mg × 10 -1 was determined by ROC analysis with the highest area under the curve (95% confidence interval): 0.956 (0.915-0.997), P < 0.001. When compared with the guideline-recommended cut-off (UNa + <50 mmol/L as a reference, specificity-0.97; sensitivity-0.83), the odds ratio (OR) for UNa + /UCreat to identify a poor diuretic response was 2.5 times greater, regardless of kidney function (OR for estimated glomerular filtration rate in the logistic regression model was 0.978 [0.945-1.013, P = 0.222])., Conclusions: The UNa + /UCr ratio in a spot urine sample 2 h after intravenous diuretic administration is a simple, highly predictive marker for the identification of AHF patients with poor diuretic response, surpassing guidelines-recommended markers like UNa + ., (© 2024 The Author(s). ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: To determine the effect of stress maneuvers/interventions on ultrasound liver stiffness measurements (LSMs) in patients with Fontan circulation and healthy controls., Methods: In this prospective, IRB-approved study of 10 patients after Fontan palliation and 10 healthy controls, ultrasound 2D shear-wave elastography LSMs were acquired at baseline and after maximum inspiration, expiration, standing, handgrip, aerobic exercise, i.v. fluid (500 mL normal saline) administration, and i.v. furosemide (20 mg) administration. Absolute and percent change in LSM were compared between baseline and each maneuver, and then from fluid infusion to after diuresis., Results: Median ages were 25.5 and 26 years in the post-Fontan and control groups (p = 0.796). LSMs after Fontan were higher at baseline (2.6 vs. 1.3 m/s) and with all maneuvers compared to controls (all p < 0.001). Changes in LSM with maneuvers, exercise, fluid, or diuresis were not significant when compared to baseline in post-Fontan patients. LSM in controls increased with inspiration (+0.02 m/s, 1.6%, p = 0.03), standing (+0.07 m/s, 5.5%, p = 0.03), and fluid administration (+0.10 m/s, 7.8%, p = 0.002), and decreased 60 minutes after diuretic administration (-0.05 m/s, -3.9%, p = 0.01) compared to baseline. LSM after diuretic administration significantly decreased when compared to after i.v. fluid administration at 30 minutes (-0.79 m/s, -26.5%, p = 0.004) and 60 minutes (-0.78 m/s, -26.2%, p = 0.017) for patients after Fontan and controls at 15 minutes (-0.12 m/s, -8.70%, p = 0.002), 30 minutes (-0.15 m/s, -10.9%, p = 0.003), and 60 minutes (-0.1 m/s, -10.9%, p = 0.005)., Conclusions: LSM after Fontan is higher with more variability compared to controls. Diuresis is associated with significantly decreased liver stiffness in both patients after Fontan and controls, with the suggestion of a greater effect in Fontan patients., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

Background and Aims: In the STEP-HFpEF trial programme, treatment with semaglutide resulted in multiple beneficial effects in patients with obesity-related heart failure with preserved ejection fraction (HFpEF). Efficacy may vary according to baseline diuretic use, and semaglutide treatment could modify diuretic dose., Methods: In this pre-specified analysis of pooled data from the STEP-HFpEF and STEP-HFpEF-DM trials (n = 1145), which randomized participants with HFpEF and body mass index ≥ 30 kg/m2 to once weekly semaglutide 2.4 mg or placebo for 52 weeks, we examined whether efficacy and safety endpoints differed by baseline diuretic use, as well as the effect of semaglutide on loop diuretic use and dose changes over the 52-week treatment period., Results: At baseline, across no diuretic (n = 220), non-loop diuretic only (n = 223), and loop diuretic [<40 (n = 219), 40 (n = 309), and >40 (n = 174) mg/day furosemide equivalents] groups, there was progressively higher prevalence of hypertension and atrial fibrillation; and greater severity of obesity and heart failure. Over 52 weeks of treatment, semaglutide had a consistent beneficial effect on change in body weight across diuretic use categories (adjusted mean difference vs. placebo ranged from -8.8% [95% confidence interval (CI) -10.3, -6.3] to -6.9% [95% CI -9.1, -4.7] from no diuretics to the highest loop diuretic dose category; interaction P = .39). Kansas City Cardiomyopathy Questionnaire clinical summary score improvement was greater in patients on loop diuretics compared to those not on loop diuretics (adjusted mean difference vs. placebo: +9.3 [6.5; 12.1] vs. +4.7 points [1.3, 8.2]; P = .042). Semaglutide had consistent beneficial effects on all secondary efficacy endpoints (including 6 min walk distance) across diuretic subgroups (interaction P = .24-.92). Safety also favoured semaglutide vs. placebo across the diuretic subgroups. From baseline to 52 weeks, loop diuretic dose decreased by 17% in the semaglutide group vs. a 2.4% increase in the placebo group (P < .0001). Semaglutide (vs. placebo) was more likely to result in loop diuretic dose reduction (odds ratio [OR] 2.67 [95% CI 1.70, 4.18]) and less likely dose increase (OR 0.35 [95% CI 0.23, 0.53]; P < .001 for both) from baseline to 52 weeks., Conclusions: In patients with obesity-related HFpEF, semaglutide improved heart failure-related symptoms and physical limitations across diuretic use subgroups, with more pronounced benefits among patients receiving loop diuretics at baseline. Reductions in weight and improvements in exercise function with semaglutide vs. placebo were consistent in all diuretic use categories. Semaglutide also led to a reduction in loop diuretic use and dose between baseline and 52 weeks., Clinical Trial Registration: NCT04788511 and NCT04916470., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Objectives: In Zambia, 19.1% of the adult population had elevated blood pressure. Hence, the Ministry of Health in Zambia designated the improvement of hypertension (HTN) care services as a priority policy. However, there are limited data on cost-effective interventions to address HTN and their budget impact in sub-Saharan Africa. The objective of this paper is to investigate the cost-effectiveness of primary-level interventions for HTN (pharmaceutical treatments) compared with no treatment, and the budget impact, in the Chongwe District, rural Zambia., Methods: A cost-utility analysis was undertaken from the perspective of healthcare provider, employing a cohort Markov model with a lifetime horizon. The model was developed and populated with evidence from the literature, including novel locally collected cost data. The analysis was run for the overall population aged 40 years and above and for subpopulations stratified by three levels of risk and gender in Chongwe District by using cost data directly collected. A probabilistic analysis was performed to assess the probability of cost-effectiveness., Results: The dominant treatment for the general population was a combination therapy of diuretics and calcium blockers. The incremental cost-effectiveness ratio was US$1114 compared with no treatment. This was the most cost-effective first-line medication for HTN for all subgroup populations, except for the subgroups classified as low-risk defined by WHO. The estimated annual budget impact was US$1 015 605 in total if all HTN patients in Chongwe District received the most cost-effective treatment. Considering only material costs, the annual total budget was US$29 435., Conclusion: The most cost-effective first-line medication for HTN in rural Zambia was the combination therapy of diuretics and calcium blockers for the general population. From the perspective of budget impact, local government could need to secure approximately US$30 000 to facilitate the delivery of the most cost-effective HTN medications to the entire population over 40 years in need., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: The objectives of this study are to describe the prevalence of therapeutic use exemptions (TUEs) among athletes competing in four Olympic and four Paralympic games. The secondary objective was to present the prohibited substance and methods classes associated with TUEs., Methods: Data from the Anti-Doping Administration and Management System were extracted for this cross-sectional observation study. Eight cohorts were created to include athletes with TUEs who competed in the Rio 2016, Pyeongchang 2018, Tokyo 2020 and Beijing 2022 Olympic and Paralympic games. Prevalence of TUEs and proportion of prohibited substance and methods classes were defined as percentages among all athletes competing at each games., Results: 28 583 athletes competed in four editions of the Olympic games. Total prevalence of athletes with TUEs was 0.90% among all competitors. At the four Paralympic games, a total of 9852 athletes competed and the total TUE prevalence was 2.76%. The most frequently observed substances associated with TUEs at the Summer Olympics were glucocorticoids (0.50% in Rio) and stimulants (0.39% in Tokyo). At the Summer Paralympics, diuretics (0.79% in Rio) and stimulants (0.75% in Tokyo) were the most common. Winter games had somewhat similar trends, although TUE numbers were very low., Conclusions: The number of athletes competing with valid TUEs at the Olympic and Paralympic games was <1% and <3%, respectively. Variations in substances and methods associated with TUEs for different medical conditions were identified. Nevertheless, numbers were low, further reaffirming that TUEs are not widespread in elite sport., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

As we continue to advance in the field of medicine, the role of loop diuretics remains crucial in the management of a wide range of conditions associated with fluid retention. The introduction of torsemide has brought a new dimension to diuretic therapy, offering unique benefits that distinguish it from its counterparts., (© Journal of the Association of Physicians of India 2024.)

Heart failure (HF) is the fastest-growing disease with a higher fatality rate. The most differentiating feature of HF is pulmonary or peripheral edema, which is characterized by a gradient between intravascular and extravascular pressure. Loop diuretics were chosen as the primary treatment for edema associated with HF due to their efficacy and early onset of action. If an oral dose had not been provided, intravenous (IV) administration of torsemide, or equal doses of furosemide and bumetanide, was preferred. However, the key variables for selecting and administering loop diuretics are their pharmacological qualities as well as their clinical efficacy. Torsemide has greater bioavailability, a higher rate of absorption, a longer duration of action, and lesser ototoxicity, making it the primary choice in the management of edematous HF., (© Journal of the Association of Physicians of India 2024.)

The field of diuretic therapy has witnessed significant advancements over the decades. Loop diuretics and other diuretic agents are crucial in the management of various conditions characterized by fluid overload. Torsemide, a loop diuretic agent, has unique pharmacological properties, safety profiles, and varied clinical applications. This special journal supplement aims to provide a comprehensive examination of torsemide, highlighting its role in contemporary medical practice., (© Journal of the Association of Physicians of India 2024.)

Acute heart failure (AHF) often leads to unfavorable outcomes due to fluid overload. While diuretics are the cornerstone treatment, acetazolamide may enhance diuretic efficiency by reducing sodium reabsorption. We performed a systematic review and meta-analysis on the effects of acetazolamide as an add-on therapy in patients with AHF compared to diuretic therapy. PubMed, Embase, and Cochrane databases were searched for randomized controlled trials (RCT). A random-effects model was employed to compute mean differences and risk ratios. Statistical analysis was performed using R software. The GRADE approach was used to rate the certainty of the evidence. We included 4 RCTs with 634 patients aged 68 to 81 years. Over a mean follow-up of 3 days to 34 months, acetazolamide significantly increased diuresis (MD 899.2 mL; 95% CI 249.5 to 1549; p < 0.01) and natriuresis (MD 72.44 mmol/L; 95% CI 39.4 to 105.4; p < 0.01) after 48 h of its administration. No association was found between acetazolamide use and WRF (RR 2.4; 95% CI 0.4 to 14.2; p = 0.3) or all-cause mortality (RR 1.2; 95% CI 0.8 to 1.9; p = 0.3). Clinical decongestion was significantly higher in the intervention group (RR 1.35; 95% CI 1.09 to 1.68; p = 0.01). Acetazolamide is an effective add-on therapy in patients with AHF, increasing diuresis, natriuresis, and clinical decongestion, but it was not associated with differences in mortality., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction and Objectives: Carbohydrate antigen 125 (CA125), a biomarker associated with fluid overload, has proven useful in managing diuretic therapy in heart failure. We aimed to evaluate the impact of diuretic optimization guided by CA125 before transcatheter aortic valve implantation (TAVI) on outcomes., Methods: This prospective interventional study enrolled patients scheduled for TAVI, in whom baseline CA125 was measured 2 weeks before TAVI. Patients with CA125 ≥ 20 U/mL underwent diuretic up-titration before TAVI. Three groups were included: group I) baseline CA125 <20 U/mL; IIa) CA125 ≥ 20 U/mL that decreased after treatment, and IIb) CA125 ≥ 20 U/mL that did not decrease. The primary outcome was changes in the Kansas City Cardiomyopathy Questionnaire at 3 and 12 months. The secondary endpoint was clinical events., Results: The study included 184 patients (115 group I, 46 IIa, and 23 IIb). Groups I and IIa exhibited early and sustained improvements in the Kansas City Cardiomyopathy Questionnaire (group I: 18.9 points [95%CI, 15.7-22.1; P <.001] at 90 days, and 18.1 [95%CI, 14.9-21.4, P <.001] at 1 year; group IIa: 21.1 points [95%CI, 15.4-26.7; P <.001] and 19.5 [95%CI, 13.9-25.1; P <.001] respectively). In contrast, in group IIb there was no significant improvement at 90 days (P=.12), with improvement being significant only at 1 year (17.8 points, 95%CI, 5.9-29.6; P=.003). Over a median follow-up of 20.7 months, there were 63 (27.83%) deaths or heart failure admissions. Multivariate analysis showed a lower risk of events in group I vs IIb (HR, 0.28; 95%CI, 0.14-0.58; P <.001), and IIa vs IIb (HR, 0.24; 95%CI, 0.11-0.55; P <.001)., Conclusions: Patients with persistently high CA125 despite diuretic therapy pre-TAVI showed slower functional recovery and poorer clinical outcomes after TAVI., (Copyright © 2024 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved.)

The beneficial impacts of metabolic surgery (MS) on patients with heart failure (HF) are incompletely characterized. We aimed to describe the cardiac and metabolic effects of MS in patients with HF and hypothesized that patients with HF would experience both improved metabolic and HF profiles using glycemic control and diuretic dependency as surrogate markers. In this single-center, university-affiliated academic study in the United States, a review of 2,342 hospital records of patients who underwent MS (2017 to 2023) identified 63 patients with a medical history of HF. Preoperative characteristics, 30-day outcomes, and up to 2-year biometric and metabolic outcomes, medication usage, and emergency department utilization were collected. At 24 months, mean body mass index change was -16 kg/m 2 (p <0.001) that corresponded to a mean percentage total body weight loss of 29% (p <0.001). Weight loss was accompanied by significant reductions in hemoglobin A1c (p <0.001) and a 65% decrease in diuretic use at 24 months after surgery (p <0.001). Similarly, emergency visits for cardiac conditions (p = 0.06) and intravenous diuresis (p = 0.07) trended favorably at 1 year after surgery compared with 1 year before surgery but were not statistically significant. In conclusion, in patients with HF who were carefully selected, MS appears to provide significant reduction in oral diuretic dependency, and metabolic improvements with trends toward lower rates of emergency department utilization., Competing Interests: Declaration of competing interest Dr. Tang has served as consultant for Sequana Medical, Cardiol Therapeutics, Genomics plc, Zehna Therapeutics, WhiteSwell, Kiniksa Pharmaceuticals, Boston Scientific, CardiaTec Biosciences, Intellia Therapeutics, Bristol-Myers Squibb, Alleviant Medical, Alexion Pharmaceuticals, Salubris Biotherapeutics, and BioCardia, and has received honoraria from Springer, Belvoir Media Group, and American Board of Internal Medicine. Dr. Cook has served as consultant for Asensus Surgical, Intuitive Surgical, and Vicarious Surgical. Dr. Schauer reports receiving research grants from Ethicon and Medtronic; receiving personal consulting fees or honoraria from GI Dynamics; Keyron; Persona; Mediflix, Metabolic Health International, LTD, Lilly, Heron, Novo Nordisk, Klens; serving on scientific advisory boards for SE Healthcare Board of Directors; GI Dynamics ; Keyron; Persona; Mediflix, and having ownership interest in SE Healthcare LLC, Mediflix, Metabolic Health International, LTD. The remaining authors have no competing interests to declare., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Multicenter early diuretic response (DR) analysis of single furosemide dosing following neonatal cardiac surgery is lacking to inform whether early DR predicts adverse clinical outcomes., Methods: We performed a retrospective cohort study utilizing data from the NEPHRON registry. Random forest machine learning generated receiver operating characteristic-area under the curve (ROC-AUC) and odds ratios for mechanical ventilation (MV) and respiratory support (RS). Prolonged MV and RS were defined using ≥ 90th percentile of observed/expected ratios. Secondary outcomes were prolonged CICU and hospital length of stay (LOS) and kidney failure (stage III acute kidney injury (AKI), peritoneal dialysis, and/or continuous kidney replacement therapy on postoperative day three) assessed using covariate-adjusted ROC-AUC curves., Results: A total of 782 children were included. Cumulative urine output (UOP) metrics were lower in prolonged MV and RS patients, but DR poorly predicted prolonged MV (highest AUC 0.611, OR 0.98, sensitivity 0.67, specificity 0.53, p = 0.006, 95% OR CI 0.96-0.99 for cumulative 6-h UOP) and RS (highest AUC 0.674, OR 0.94, sensitivity 0.75, specificity 0.54, p < 0.001, 95% CI 0.91-0.97 UOP between 3 and 6 h). Secondary outcome results were similar. DR had fair discrimination for kidney failure (AUC 0.703, OR 0.94, sensitivity 0.63, specificity 0.71, 95% OR CI 0.91-0.98, p < 0.001, cumulative 6-h UOP)., Conclusions: Early DR poorly discriminated patients with prolonged MV, RS, and LOS in this cohort, though it may identify severe postoperative AKI phenotype. Future work is warranted to determine if early DR or late postoperative DR later, in combination with other AKI metrics, may identify a higher-risk phenotype., (© 2024. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

Incomplete decongestion is the main cause of readmission in the early post-discharge period of a hospitalization for acute heart failure. Recent heart failure guidelines have highlighted initiation and rapid up-titration of quadruple therapy with angiotensin receptor neprilysin inhibitor, beta adrenergic receptor blocker, mineralocorticoid receptor antagonist, and sodium glucose cotransporter 2 inhibitor to prevent hospitalizations for heart failure with reduced ejection fraction. However, full decongestion remains the foremost therapeutic goal of hospitalization for heart failure. While early addition of sodium glucose cotransporter 2 inhibitors and mineralocorticoid receptor antagonists may be helpful, the value of the other therapeutics comes after decongestion is complete., Competing Interests: Declaration of competing interest The authors report no relationships that could be construed as a conflict of interest. The study was not supported by any funding sources., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The polyuria and polydipsia state in diabetes insipidus (DI) can be challenging to manage for patients and clinicians with significant impact on the patients' well-being. A review of literature shows that nonsteroidal anti-inflammatory drugs (NSAIDs), thiazide and potassium-sparing diuretics, along with low dietary solute and protein, and high water intake remain the standard medical therapy. Although these therapeutic approaches improve symptoms, the urine-concentrating defect is still considerable, posing a serious risk to patient's life from hypovolemia if high fluid intake is not maintained. Our case describes the challenges faced with the medical management of a patient with nephrogenic DI that was only partially responsive to standard medical therapy, resulting in debilitating effects on the patient's quality of life.

There are no nationwide surveys on antihypertensive drugs in China. In order to assess the current status of antihypertensive drug therapy in patients with hypertension and analyzed factors that may affect combination therapy, using convenience sampling, we recruited 305,624 patients with hypertension from the Chinese Cardiovascular Association Database-Hypertension Center between January 2019 and December 2021. Chi-squared test was performed to analyze the administered antihypertensive drug types and their combinations in different hospital settings. Logistic regression was used to assess the factors influencing combination therapy. We found around 33.1% of the participants had stage 2 and above hypertension, of which 67.9% were treated with combination therapy. In community or general hospitals, the most common monotherapy was calcium channel blockers (CCB), angiotensin-converting enzyme inhibitor/angiotensin II receptor inhibitor (ACEI/ARB) and diuretic were the main single-pill combinations (SPCs), and ACEI/ARB and CCB were the main free combination. From 2019 to 2021, the rates of combination therapy increased (58.8%-64.1%) with SPCs from 25.9% to 31.0% and free combination from 31.9% to 32.6%. Patients aged < 60 years, with stage 2 and above hypertension, with an education level of high school and above, visiting general hospitals, living in the eastern region of China, with hypertension risk factors and comorbidities, and without anxiety or depression were more likely to receive combination therapy (all P < .05). The combination therapy use rate increased yearly and the rate of SPCs rose obviously. Individual, hospital, and regional differences in patients with hypertension influenced combination therapy., (© 2024 The Author(s). The Journal of Clinical Hypertension published by Wiley Periodicals LLC.)

Background: Differentiating between intrinsic and prerenal acute kidney injury (AKI) presents a challenge. Here, we assessed the performance of the fractional excretion of urea (FEUrea) and compared it to the fractional excretion of sodium (FENa) in distinguishing intrinsic from prerenal AKI., Methods: A thorough search was conducted in several databases until January 16, 2024. We included studies evaluating FEUrea, with or without FENa, for differentiating AKI etiologies in adults. We assessed the methodological quality using the QUADAS-2 and QUADAS-C tools. We performed a meta-analysis using the bivariate random effects model, with subgroup analyses to explore the impact of diuretic therapy on FEUrea, and direct statistical comparisons between FEUrea and FENa involving the subgroups with and without diuretics., Results: We included 11 studies with 1108 hospitalized patients. Among eight studies (915 patients) evaluating FEUrea >35% for distinguishing intrinsic from prerenal AKI, the pooled sensitivity and specificity were 66% (95% CI, 49%-79%) and 75% (95% CI, 60%-85%), respectively. In a subset of six studies (302 patients) comparing FEUrea at 35% to FENa at 1% in patients not receiving diuretics, there were no significant differences in sensitivity (77% versus 89%, P = 0.410) or specificity (80% versus 79%, P = 0.956). In four studies, 244 patients on diuretics, FEUrea demonstrated lower sensitivity (52% versus 92%, P < 0.001) but higher specificity (82% versus 44%, P < 0.001) compared to FENa for the diagnosis of intrinsic AKI., Conclusions: FEUrea has limited utility in differentiating intrinsic from prerenal AKI. FEUrea does not provide a superior alternative to FENa, even in patients receiving diuretics., Competing Interests: Declaration of competing interest All authors have nothing to disclose., (Copyright © 2024 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved.)

Background and Aims: There is a gap in knowledge about implementing diagnostic tools and therapy for heart failure with preserved ejection fraction (HFpEF) in clinical practice. This survey aimed to assess real-world practice in HFpEF diagnosis and treatment in the international medical community., Methods: An independent academic web-based 29-question survey was designed by a group of heart failure specialists and posted by email and through scientific societies and social networks to a broad community of physicians worldwide., Results: 1.460 physicians from 95 countries answered the survey, with a mean age of 42.2±10.4 years, 39.4 % females, and 85.1 % were cardiologists. The left ventricular ejection fraction cut-off value selected for HFpEF diagnosis was 50 % for 89 % of participants. The scores for the probability of diagnosis of HFpEF were used only by 47.2 %, and H2FPEF was the most used score (31 %). Natriuretic peptides were used by 87.4 % of participants for the diagnostic workup, while the diastolic stress test was only used by 26.2 %. 54.4 % of participants chose SGLT2 inhibitors as their first drug treatment, followed by diuretics (18.6 %) and ACE inhibitors (8.4 %)., Conclusions: In an international academic survey on HFpEF management, the criteria for screening and diagnosis of HFpEF patients remain aligned with classic international guidelines with a low use of diagnostic scores. SGLT2i is the leading therapeutic drug class used for this heterogeneous patient population. These results raise the need to improve education and awareness on diagnosing and managing HFpEF patients., Competing Interests: Declaration of competing interest CS has received honoraria as speaker for Speaker for Novartis, Servier, Merck, Sanofi Pfizer, Astrazeneca, Boehringer Ingelheim, Novo Nordisk, Ely Lilly and as advisor for Bayer, Merck and Novo Nordisk, CF has received travel fees from Pfizer, NM has received consulting fees from Bayer and Amgen and as speaker for Astrazeneca, Novartis and Boehringer Ingelheim, support for attending meetings from Astrazeneca and Novartis, FR has not received personal payments by pharmaceutical companies or device manufacturers in the last 3 years (remuneration for the time spent in activities, such as participation as steering committee member of clinical trials and member of the Pfizer Research Award selection committee in Switzerland, were made directly to the University of Zurich). The Department of Cardiology (University Hospital of Zurich/University of Zurich) reports research-, educational- and/or travel grants from Abbott, Abiomed, Alnylam,Amarin, Amgen, Astra Zeneca, At the Limits Ltd., Bayer, Biotronik, BMS, Boehringer Ingelheim, Boston Scientific, Bracco, CM Microport, Concept Medical, CTI, Daiichi Sankyo, Edwards Lifesciences, FomF GmbH, Hamilton Health Sciences, IHF, Innosuisse, IumiraDX, Kantar, LabPoint, MedAlliance, Medcon International, Medical Education Global Solutions, Medtronic, MicroPort, Monocle, Novartis, Novo Nordisk, OM Pharma, Pfizer, Quintiles Switzerland Sarl, RecorMedical, Roche Diagnostics, Roche Pharma, Sahajanand IN, Sanofi, Sarstedt AG, Servier, Terumo Deutschland, Trama Solutions, V- Wave, Vifor, ZOLL. These grants do not impact on Prof. Ruschitzka`s personal remuneration. IJI received support for travel to meetings from Novartis. DM received payment as a speaker for Novartis, Pfizer, Astra Zeneca and support for attending meetings from Pfizer, Astrazeneca and abbot. GR reports grants and personal fees from Astra Zeneca, personal fees and other from Boheringer Ingelheim, other from Bayer, personal fees from Anlylam, other from Medtronic, grants from Servier, grants and non-financial support from Menarini, personal fees from Viatris, grants from Vifor Pharma, outside the submitted work. GGR reports personal fees from Pfizer, personal fees from CSL Vifor, personal fees from Astra Zeneca, personal fees from PTC therapeutics, personal fees from Bristol MS, personal fees from Boehringer Ingelheim, personal fees from Servier, outside the submitted work; GE reports personal fees from NOVO NORDISK, during the conduct of the study; IM reports grants from Boehringer Ingelheim, during the conduct of the study, SZ Served on advisory boards for, or speaker engagements with Abbott, AstraZeneca, Bayer, BMS, Boehringer Ingelheim, Cytokinetics, Eli Lilly, GSK, Medtronic, Merck, Novartis, Novo-Nordisk, Pfizer and Vifor Pharma; and serves on a clinical trial committee or as a national lead for studies sponsored by AstraZeneca, Boehringer Ingelheim, Merck, Novartis, Pfizer, Salubris Bio and Served on advisory boards for, or speaker engagements with Abbott, AstraZeneca, Bayer, BMS, Boehringer Ingelheim, Cytokinetics, Eli Lilly, GSK, Medtronic, Merck, Novartis, Novo-Nordisk, Pfizer and Vifor Pharma., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Importance: Hypertension is increasingly common in pregnancy capable individuals, yet there is limited data on antihypertensive medication dispensation in peripartum individuals., Objective: To describe antihypertensive medication dispensation from preconception through the first year postpartum., Design, Setting, and Participants: This retrospective cohort study used the Truven Health Market Scan administrative data from 2008 to 2014 to identify women in the United States with commercial or government health insurance, aged 15-54, free from heart disease, who experienced a pregnancy and filled at least 1 prescription for an antihypertensive medication between 3 months prior to conception and 12 months after the end of the pregnancy., Main Outcomes and Measures: We describe antihypertensive dispensation patterns (continuation, initiation, and discontinuation) by medication class during 5 time periods: preconception, first, second, and third trimesters, and the first year postpartum., Results: Of 1,058,521 pregnancies, 108,614 (10.3%) were exposed to at least 1 antihypertensive medication dispensation. The most commonly dispensed medications across all periods combined were adrenergic blockers, calcium channel blockers (CCBs), and diuretics. Renin-angiotensin-aldosterone system (RAAS) inhibitors were the third most dispensed medication class in the preconception period (26.4%), and fills decreased to 5.7% and 1.7% in the second and third trimesters, respectively. Of the women with chronic hypertension who filled at least 1 prescription prior to conception, 8.4% were not dispensed an antihypertensive medication during the first year after delivery., Conclusions and Relevance: Antihypertensive prescription dispensation of both preferred and potentially harmful agents is common in pregnancy capable individuals. Patterns of dispensation suggest room for improvement in the treatment of chronic hypertension after a pregnancy., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Volume overload represents a hallmark clinical feature linked to the development and progression of heart failure (HF). Alleviating signs and symptoms of volume overload represents a foundational HF treatment target that is achieved using loop diuretics in the acute and chronic setting. Recent work has provided evidence to support guideline-directed medical therapies, such as sodium glucose cotransporter 2 (SGLT2) inhibitors and mineralocorticoid receptor (MR) antagonists, as important adjunct diuretics that may act synergistically when used with background loop diuretics in people with chronic HF. Furthermore, there is growing interest in understanding the role of SGLT2 inhibitors, carbonic anhydrase inhibitors, thiazide diuretics, and MR antagonists in treating volume overload in patients hospitalized for acute HF, particularly in the setting of loop diuretic resistance. Thus, the current review demonstrates that: (i) SGLT2 inhibitors and MR antagonists confer long-term cardioprotection in chronic HF patients but it is unclear whether natriuresis or diuresis represents the primary mechanisms for this benefit, (ii) SGLT2 inhibitors, carbonic anhydrase inhibitors, and thiazide diuretics increase natriuresis in the acute HF setting, but implications on long-term outcomes remain unclear and warrants further investigation, and (iii) a multi-nephron segment approach, using agents that act on distinct segments of the nephron, potentiate diuresis to alleviate signs and symptoms of volume overload in acute HF., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)