Diuretic Treatment in Patients with Heart Failure: Current Evidence and Future Directions - Part I: Loop Diuretics.

PURPOSE OF REVIEW: Fluid retention or congestion is a major cause of symptoms, poor quality of life, and adverse outcome in patients with heart failure (HF). Despite advances in disease-modifying therapy, the mainstay of treatment for congestion-loop diuretics-has remained largely unchanged for 50 years. In these two articles (part I: loop diuretics and part II: combination therapy), we will review the history of diuretic treatment and the current trial evidence for different diuretic strategies and explore potential future directions of research. RECENT FINDINGS: We will assess recent trials including DOSE, TRANSFORM, ADVOR, CLOROTIC, OSPREY-AHF, and PUSH-AHF amongst others, and assess how these may influence current practice and future research. There are few data on which to base diuretic therapy in clinical practice. The most robust evidence is for high dose loop diuretic treatment over low-dose treatment for patients admitted to hospital with HF, yet this is not reflected in guidelines. There is an urgent need for more and better research on different diuretic strategies in patients with HF.

Diuretic Treatment in Patients with Heart Failure: Current Evidence and Future Directions-Part II: Combination Therapy.

PURPOSE OF REVIEW: Fluid retention or congestion is a major cause of symptoms, poor quality of life, and adverse outcome in patients with heart failure (HF). Despite advances in disease-modifying therapy, the mainstay of treatment for congestion-loop diuretics-has remained largely unchanged for 50 years. In these two articles (part I: loop diuretics and part II: combination therapy), we will review the history of diuretic treatment and current trial evidence for different diuretic strategies and explore potential future directions of research. RECENT FINDINGS: We will assess recent trials, including DOSE, TRANSFORM, ADVOR, CLOROTIC, OSPREY-AHF, and PUSH-AHF, and assess how these may influence current practice and future research. There are few data on which to base diuretic therapy in clinical practice. The most robust evidence is for high-dose loop diuretic treatment over low-dose treatment for patients admitted to hospital with HF, yet this is not reflected in guidelines. There is an urgent need for more and better research on different diuretic strategies in patients with HF.

Heterogeneous brain distribution of bumetanide following systemic administration in rats.

Bumetanide is used widely as a tool and off-label treatment to inhibit the Na-K-2Cl cotransporter NKCC1 in the brain and thereby to normalize intra-neuronal chloride levels in several brain disorders. However, following systemic administration, bumetanide only poorly penetrates into the brain parenchyma and does not reach levels sufficient to inhibit NKCC1. The low brain penetration is a consequence of both the high ionization rate and plasma protein binding, which restrict brain entry by passive diffusion, and of brain efflux transport. In previous studies, bumetanide was determined in the whole brain or a few brain regions, such as the hippocampus. However, the blood-brain barrier and its efflux transporters are heterogeneous across brain regions, so it cannot be excluded that bumetanide reaches sufficiently high brain levels for NKCC1 inhibition in some discrete brain areas. Here, bumetanide was determined in 14 brain regions following i.v. administration of 10 mg/kg in rats. Because bumetanide is much more rapidly eliminated by rats than humans, its metabolism was reduced by pretreatment with piperonyl butoxide. Significant, up to 5-fold differences in regional bumetanide levels were determined with the highest levels in the midbrain and olfactory bulb and the lowest levels in the striatum and amygdala. Brain:plasma ratios ranged between 0.004 (amygdala) and 0.022 (olfactory bulb). Regional brain levels were significantly correlated with local cerebral blood flow. However, regional bumetanide levels were far below the IC50 (2.4 µM) determined previously for rat NKCC1. Thus, these data further substantiate that the reported effects of bumetanide in rodent models of brain disorders are not related to NKCC1 inhibition in the brain.

Efficacy of tolvaptan in postoperative volume therapy for acute Stanford type A aortic dissection.

BACKGROUND: Despite the increasing application of tolvaptan in cardiac surgery, there is no information on the use of tolvaptan in Stanford patients with type A aortic dissection. This study aimed to evaluate the postoperative clinical effects of tolvaptan in patients with type A aortic dissection  after tafter surgery. METHODS: A retrospective analysis was performed on 45 patients treated for type A aortic dissection in our hospital from 2018 to 2020. These included 21 patients who were treated with tolvaptan (Group T) and 24 patients who received traditional diuretics (Group L). The hospital's electronic health records were used to obtain perioperative data. RESULTS: Group T did not differ significantly from Group L in terms of the duration of mechanical ventilation, postoperative blood required, length of catecholamine use, or the amount of intravenous diuretic drugs administered (all P > 0.05). The development of postoperative atrial fibrillation was significantly less in the tolvaptan group (P = 0.023). The urine volumes and change in body weight loss were slightly higher in group T than in group L but the differences were non-significant (P > 0.05). Serum potassium, creatinine, and urea nitrogen levels did not differ between the groups in the week after surgery, At the same time, sodium was significantly higher in the Group T group on day 7 after transfer from the ICU (P = 0.001). In Group L, sodium levels were also elevated by day 7 (P = 0.001). On days 3 and 7, serum creatinine and urea nitrogen levels increased in both groups (both P < 0.05). CONCLUSIONS: Both tolvaptan and traditional diuretics were found to be effective and safe for patients with acute Stanford type A aortic dissection. Moreover, tolvaptan may be associated with reducing the incidence of postoperative atrial fibrillation.

SGLT2 inhibitor and loop diuretic induce different vasopressin and fluid homeostatic responses in nondiabetic rats.

Loop diuretics are commonly used diuretics in the treatment of fluid retention but induce hypovolemia-related renal dysfunction. Na+-glucose cotransporter 2 (SGLT2) inhibitors induce osmotic diuresis, but body fluid volume is maintained by stimulating vasopressin-induced fluid intake and collecting duct water reabsorption as previously reported in diabetic rats. We aimed to test the hypothesis that unlike SGLT2 inhibitors, loop diuretics lack activation of similar fluid homeostatic mechanisms. Nondiabetic male Sprague-Dawley rats were treated daily by oral gavage with vehicle, the SGLT2 inhibitor ipragliflozin (5 mg/kg), or the loop diuretic furosemide (50 mg/kg) and monitored in metabolic cages for 2 or 7 days. Ipragliflozin and furosemide similarly increased urine volume on day 2. This was associated with increased serum Na+ concentration, urine vasopressin excretion, fluid intake, and solute-free water reabsorption in response to ipragliflozin but not to furosemide. Ipragliflozin maintained fluid balance (fluid intake - urine volume) on day 2 and total body water measured by bioimpedance spectroscopy and serum creatinine on day 7. In comparison, furosemide decreased fluid balance on day 2 and decreased total body water and increased serum creatinine on day 7. Furosemide, but not ipragliflozin, increased plasma renin activity, and systolic blood pressure was similar among the groups. In conclusion, the osmotic diuresis of the SGLT2 inhibitor increased serum Na+ concentration and the vasopressin-related stimulation of fluid intake and renal water retention maintained fluid balance, whereas the loop diuretic did not engage the compensatory vasopressin system. The data suggest differences in vasopressin and fluid homeostatic responses between SGLT2 inhibitors and loop diuretics.NEW & NOTEWORTHY In nondiabetic rats, the Na+-glucose cotransporter 2 (SGLT2) inhibitor ipragliflozin increased vasopressin-related stimulation of fluid intake and free water reabsorption and maintained fluid balance and serum creatinine, whereas the loop diuretic furosemide reduced vasopressin and induced a negative fluid balance followed by a subsequent increase in serum creatinine. This study suggests that differences in vasopressin secretion in response to a SGLT2 inhibitor or loop diuretic may contribute to differences in body fluid status and subsequent renal function.

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.

Safety of torasemide in healthy adult dogs administered daily for 26 weeks.

Thirty-two (16 males and 16 females) healthy young beagles were randomly divided into four groups of eight. The control group remained untreated. Torasemide (ISEMID® , Ceva Santé Animale) was orally administered, once daily, at 0.5 mg/kg from Days 1-5 then 0.25 mg/kg to Day 182, and at three times and five times this dosing regimen in two additional groups. Treated animals (predominantly at the higher dose levels) showed dryness of the oral mucosa, evidence of diuresis, decreased diet consumption, decreased bodyweight gain over the first 3 weeks, increased water consumption, increases in erythrocytes count, haemoglobin, calcium and magnesium, decrease in chloride, phosphorus, potassium and sodium, increases in urine pH, decreases in urine specific gravity and increases in serum aldosterone concentrations. Plasma concentrations of torasemide increased in a dose-dependent manner and showed no evidence of accumulation. There were also changes to electrocardiogram patterns and the macroscopic and microscopic appearance of the kidney and adrenal glands, but these changes were almost exclusively confined to the over-dosed groups. In conclusion, torasemide was found to be safe when administered to dogs at 0.25 mg/kg once daily for 26 weeks, and any changes were consistent with its known diuretic effects.

Soluble CD146-an underreported novel biomarker of congestion: a comment on a review concerning congestion assessment and evaluation in acute heart failure.

In spite of high prevalence, congestion remains a poorly understood phenomenon in heart failure pathophysiology. Its negative impact on outcome has been widely recognised. Still, data from various registries reveal the failure of the contemporary treatment strategies to overcome congestion. This shortcoming is closely related to the fact that there are no universe means for congestion assessment and grading, making it a difficult process to recognise. CD146 is a novel blood biomarker of congestion that has been shown to reflect intravascular fluid accumulation in a number of experimental and clinical studies. This observation deserves special attention, given the huge gap of knowledge about decongestive strategies in acute and chronic heart failure. Randomised clinical trials testing the effect of CD146-guided management intervention are urgently needed to estimate its value in heart failure care.

Pharmacokinetics and diuretic effect of furosemide after single intravenous, oral tablet, and newly developed oral disintegrating film administration in healthy beagle dogs.

BACKGROUND: Furosemide, a diuretic that acts on the loop of Henle, is commonly used to treat congestive heart failure in veterinary medicine. Some owners have difficulty in administering oral tablet medication to animal patients, which leads to noncompliance, especially during long-term administration. Oral disintegrating film (ODF) has the advantages of easy administration via a non-invasive route, rapid dissolution, and low suffocating risk. The objective of this study was to research the pharmacokinetic (PK) profiles and diuretic effect of furosemide after intravenous (IV), orally uncoated tablet (OUT), and newly developed ODF administration in healthy beagle dogs. In this study, a furosemide-loaded ODF (FS-ODF) formulation was developed and five beagle dogs were administered a single dose (2 mg/kg) of furosemide via each route using a cross-over design. RESULTS: The most suitable film-forming agent was sodium alginate; thus, this was used to develop an ODF for easy drug administration. No significant differences were detected in the PK profiles between OUT and FS-ODF. In the blood profiles, the concentration of total protein was significantly increased compared to the baseline (0 h), whereas no significant difference was detected in the concentration of creatinine and hematocrit compared to the baseline. FS-ODF resulted in a similar hourly urinary output to OUT during the initial 2 h after administration. The urine specific gravity was significantly decreased compared to the baseline in each group. The peak times of urine electrolyte (sodium and chloride) excretion per hour were 1 h (IV), 2 h (OUT), and 2 h (FS-ODF). CONCLUSIONS: These results suggest that the PK/PD of furosemide after administration of newly developed FS-ODF are similar to those of OUT in healthy dogs. Therefore, the ODF formulation has the benefits of ease and convenience, which would be helpful to owners of companion animals, such as small dogs (< 10 kg), for the management of congestive heart failure.

Efficacy of Furosemide, Oral Sodium Chloride, and Fluid Restriction for Treatment of Syndrome of Inappropriate Antidiuresis (SIAD): An Open-label Randomized Controlled Study (The EFFUSE-FLUID Trial).

RATIONALE & OBJECTIVE: First-line therapy for syndrome of inappropriate antidiuresis (SIAD) is fluid restriction. Additional treatment for patients who do not respond to fluid restriction are water restriction with furosemide or water restriction with furosemide and salt supplementation. However, the efficacy of these treatments has never been tested in a randomized controlled study. The objective of this study was to investigate whether, combined with fluid restriction, furosemide with or without sodium chloride (NaCl) supplementation was more effective than fluid restriction alone in the treatment of hyponatremia in SIAD. STUDY DESIGN: Open-label randomized controlled study. SETTING & PARTICIPANTS: Patients with serum sodium concentrations ([Na+]) ≤ 130mmol/L due to SIAD. INTERVENTION(S): Random assignment to 1 of 3 groups: fluid restriction alone (FR), fluid restriction and furosemide (FR+FM), or fluid restriction, furosemide, and NaCl (FR+FM+NaCl). Strictness of fluid restriction (<1,000 or<500mL/d) was guided by the urine to serum electrolyte ratio. Furosemide dosage was 20 to 40mg/d. NaCl supplements were 3g/d. All treatments were continued for 28 days. OUTCOMES: The primary outcome was change in [Na+] at days 4, 7, 14, and 28 after randomization. RESULTS: 92 patients were recruited (FR, n=31; FR+FM, n=30; FR+FM+NaCl, n=31). Baseline [Na+] was 125±4mmol/L, and there were no significant differences between groups. Mean [Na+] on day 4 in all treatment groups was significantly increased from baseline by 5mmol/L (P<0.001); however, the change in [Na+] was not significantly different across groups (P=0.7). There was no significant difference in percentage of patients or time to reach [Na+] ≥ 130 or≥135mmol/L across the 3 groups. Acute kidney injury and hypokalemia (potassium≤3.0mmol/L) were more common in patients receiving furosemide. LIMITATIONS: Open-label treatment. CONCLUSIONS: In patients with SIAD, furosemide with NaCl supplement in combination with fluid restriction did not show benefits in correction of [Na+] compared with treatment with fluid restriction alone. Incidences of acute kidney injury and hypokalemia were increased in patients receiving furosemide. FUNDING: None. TRIAL REGISTRATION: Registered at the Thai Clinical Trial Registry with study number TCTR20170629004.

Loop diuretic resistance complicating acute heart failure.

Acute heart failure hospitalizations complicated by diuretic resistance are associated with worse outcomes. Yet, quantification of the frequency and accompanying risk from loop diuretic resistance is limited by the absence of a comprehensive definition with universal clinical application. Herein, we outline limitations of the current metrics used to identify and define diuretic resistance. We discuss the best available methods to identify and prognosticate outcomes in diuretic resistance. We propose a mechanism-based classification system of diuretic resistance by anatomical location as follows: pre-nephron resistance, pre-loop of Henle resistance, loop of Henle resistance, and post-loop of Henle resistance. Within this paradigm, we compare and contrast historical beliefs of resistance mechanisms with current literature specific to patients with heart failure. We recommend a treatment pathway to restore diuretic efficacy with a literature review of the various combination diuretic strategies and ongoing clinical trials that may impact current best practices.

Renal Nerve Deafferentation Attenuates the Fall in GFR during Intravenous Infusion of Furosemide in Anesthetized Rats.

INTRODUCTION: Furosemide reduces the glomerular filtration rate (GFR) and increases the renal vascular resistance (RVR) despite inhibiting tubuloglomerular feedback but increases proximal tubule pressure, renin release, and renal nerve activity. OBJECTIVE: This study tested the hypothesis that the fall in GFR with furosemide is due to volume depletion or activation of angiotensin type 1 (AT1) receptors or renal nerves. METHODS: Furosemide was infused for 60 min at 1.0 mg·kg-1·h-1 in groups of 5-8 anesthetized rats. Additional groups received intravenous volume replacement to prevent fluid and Na+ losses or volume replacement plus losartan or plus sham denervation or plus renal denervation or renal nerve deafferentation. RESULTS: At 60 min of infusion, furosemide alone reduced the GFR (-37 ± 4%; p < 0.01). This fall was not prevented by volume replacement or pretreatment with losartan, although losartan moderated the increase in RVR with furosemide (+44 ± 3 vs. +82 ± 7%; p < 0.01). Whereas the GFR fell after furosemide in rats after sham procedure (-31 ± 2%), it was not changed significantly after prior renal deafferentation. Proximal tubule pressure increased significantly but returned towards baseline over 60 min of furosemide, while urine output remained elevated, and GFR and renal blood flow depressed. CONCLUSIONS: The fall in GFR over 60 min of furosemide infusion is independent of volume depletion or activation of AT1 receptors but is largely dependent on renal afferent nerves.

Impact of loop diuretics on critically ill patients with a positive fluid balance.

The impact of the use of loop diuretics to prevent cumulative fluid balance in non-oliguric patients is uncertain. This is a retrospective study to estimate the association of time-averaging loop diuretic exposure in a large population of non-cardiac, critically ill patients with a positive fluid balance (> 5% of body weight). The exposure was loop diuretic and the main outcomes were 28-day mortality, severe acute kidney injury and successful mechanical ventilation weaning. Time-fixed and daily time-varying variables were evaluated with a marginal structural Cox model, adjusting bias for time-varying exposure and the presence of time-dependent confounders. A total of 14,896 patients were included. Patients receiving loop diuretics had better survival (unadjusted hazard ratio 0.56, 95%CI 0.39-0.81 and baseline variables adjusted hazard ratio 0.53, 95%CI 0.45-0.62); after full adjusting, loop diuretics had no association with 28-day mortality (full adjusted hazard ratio 1.07, 95%CI 0.74-1.54) or with reducing severe acute kidney injury occurrence during intensive care unit stay - hazard ratio 1.05 (95%CI 0.78-1.42). However, we identified an association with prolonged mechanical ventilation (hazard ratio 1.59, 95%CI 1.35-1.89). The main results were consistent in the sub-group analysis for sepsis, oliguria and the study period (2002-2007 vs. 2008-2012). Also, equivalent doses of up to 80 mg per day of furosemide had no significant association with mortality. After adjusting for time-varying variables, the time average of loop diuretic exposure in non-cardiac, critically ill patients has no association with overall mortality or severe acute kidney injury; however, prolonged mechanical ventilation is a concern.

Drugs Causing Bone Loss.

Drugs may cause bone loss by lowering sex steroid levels (e.g., aromatase inhibitors in breast cancer, GnRH agonists in prostate cancer, or depot medroxyprogestone acetate - DMPA), interfere with vitamin D levels (liver inducing anti-epileptic drugs), or directly by toxic effects on bone cells (chemotherapy, phenytoin, or thiazolidinedions, which diverts mesenchymal stem cells from forming osteoblasts to forming adipocytes). However, besides effects on the mineralized matrix, interactions with collagen and other parts of the unmineralized matrix may decrease bone biomechanical competence in a manner that may not correlate with bone mineral density (BMD) measured by dual energy absorptiometry (DXA).Some drugs and drug classes may decrease BMD like the thiazolidinediones and consequently increase fracture risk. Other drugs such as glucocorticoids may decrease BMD, and thus increase fracture risk. However, glucocorticoids may also interfere with the unmineralized matrix leading to an increase in fracture risk, not mirrored in BMD changes. Some drugs such as selective serotonin reuptake inhibitors (SSRI), paracetamol, and non-steroidal anti-inflammatory drugs (NSAIDs) may not per se be associated with bone loss, but fracture risk may be increased, possibly stemming from an increased risk of falls stemming from effects on postural balance mediated by effects on the central nervous system or cardiovascular system.This paper performs a systematic review of drugs inducing bone loss or associated with fracture risk. The chapter is organized by the Anatomical Therapeutic Chemical (ATC) classification.

Loop diuretics in chronic heart failure: how to manage congestion?

Loop diuretics remain the cornerstone of congestion management in contemporary chronic heart failure care. However, their use is not supported by high quality data, and there is doubt about the safety in the outpatient heart failure setting. Still, congestion is related to a worse outcome, and there is general consensus among experts that congestion should not be tolerated in heart failure patients. Recommendations in international guidelines, regarding decongestion strategies in chronic heart failure, are limited. Thus, there is an emerging need for clinical decision-making support about the best strategy for using loop diuretics and decongestion in the chronic setting. The present review provides a comprehensive overview over the evidence of chronic loop diuretic use. Strategies for the assessment of congestion in the outpatient setting and decongestion algorithm are provided to assist health care specialists in delivering high-quality heart failure care.

Comparative Analysis of Long-Term Outcomes of Torasemide and Furosemide in Heart Failure Patients in Heart Failure Registries of the European Society of Cardiology.

PURPOSE: Current clinical recommendations do not emphasise superiority of any of diuretics, but available reports are very encouraging and suggest beneficial effects of torasemide. This study aimed to compare the effect of torasemide and furosemide on long-term outcomes and New York Heart Association (NYHA) class change in patients with chronic heart failure (HF). METHODS: Of 2019 patients enrolled in Polish parts of the heart failure registries of the European Society of Cardiology (Pilot and Long-Term), 1440 patients treated with a loop diuretic were included in the analysis. The main analysis was performed on matched cohorts of HF patients treated with furosemide and torasemide using propensity score matching. RESULTS: Torasemide was associated with a similar primary endpoint (all-cause death; 9.8% vs. 14.1%; p = 0.13) occurrence and 23.8% risk reduction of the secondary endpoint (a composite of all-cause death or hospitalisation for worsening HF; 26.4% vs. 34.7%; p = 0.04). Treatment with both torasemide and furosemide was associated with the significantly most frequent occurrence of the primary (23.8%) and secondary (59.2%) endpoints. In the matched cohort after 12 months, NYHA class was higher in the furosemide group (p = 0.04), while furosemide use was associated with a higher risk (20.0% vs. 12.9%; p = 0.03) of worsening ≥ 1 NYHA class. Torasemide use impacted positively upon the primary endpoint occurrence, especially in younger patients (aged < 65 years) and with dilated cardiomyopathy. CONCLUSIONS: Our findings contribute to the body of research on the optimal diuretic choice. Torasemide may have advantageous influence on NYHA class and long-term outcomes of HF patients, especially younger patients or those with dilated cardiomyopathy, but it needs further investigations in prospective randomised trials.

Oral Metolazone Versus Intravenous Chlorothiazide as an Adjunct to Loop Diuretics for Diuresis in Acute Decompensated Heart Failure With Reduced Ejection Fraction.

Background: Thiazide diuretics are often utilized to overcome loop diuretic resistance when treating acute decompensated heart failure (ADHF). In addition to a large cost advantage, several pharmacokinetic advantages exist when administering oral metolazone (MTZ) compared with intravenous (IV) chlorothiazide (CTZ), yet many providers are reluctant to utilize an oral formulation to treat ADHF. The purpose of this study was to compare the increase in 24-hour total urine output (UOP) after adding MTZ or CTZ to IV loop diuretics (LD) in patients with heart failure with reduced ejection fraction (HFrEF). Methods and Results: From September 2013 to August 2016, 1002 patients admitted for ADHF received either MTZ or CTZ in addition to LD. Patients were excluded for heart failure with preserved ejection fraction (HFpEF) (n = 469), <24-hour LD or UOP data prior to drug initiation (n = 129), or low dose MTZ/CTZ (n = 91). A total of 168 patients were included with 64% receiving CTZ. No significant difference was observed between the increase in 24-hour total UOP after MTZ or CTZ initiation (1458 [514, 2401] mL vs 1820 [890, 2750] mL, P = .251). Conclusions: Both MTZ and CTZ similarly increased UOP when utilized as an adjunct to IV LD. These results suggest that while thiazide agents can substantially increase UOP in ADHF patients with HFrEF, MTZ and CTZ have comparable effects.

Increased Fracture Risk with Furosemide Use in Children with Congenital Heart Disease.

OBJECTIVES: To determine the association of furosemide therapy with the incidence of bone fractures in children with congenital heart disease. STUDY DESIGN: We conducted a retrospective cohort study with data extracted from the 2008-2014 Texas Medicaid databases. Pediatric patients aged <12 years diagnosed with congenital heart disease, cardiomyopathy, or heart failure were included. Patients taking furosemide were categorized into a furosemide-adherent group (medication possession ratio of ≥70%), and a furosemide-nonadherent group (medication possession ratio of <70%). A third group of patients was matched to the furosemide user groups by using propensity score matching. A multivariate logistic regression and Cox proportional hazard model with a Kaplan-Meier plot (time-to-fracture) were used to compare the 3 groups, controlling for baseline demographics and clinical characteristics. RESULTS: After matching, 3912 patients (furosemide adherent, n = 254; furosemide nonadherent, n = 724; no furosemide, n = 2934) were identified. The incidence of fractures was highest for the furosemide-adherent group (9.1%; 23 of 254), followed by the furosemide-nonadherent group (7.2%; 52 of 724), which were both higher than for patients who did not receive furosemide (5.0%; 148 of 2934) (P < .001). Using logistic regression, both furosemide groups were more likely to have fractures than the no furosemide group: furosemide-adherent OR of 1.9 (95% CI, 1.17-2.98; P = .009); furosemide nonadherent OR of 1.5 (95% CI, 1.10-2.14; P = .01). In the Cox proportional hazard model, the risk of fractures for the furosemide-adherent group was significantly higher compared with the no furosemide group (HR, 1.6; 95% CI, 1.00-2.42; P = .04). CONCLUSIONS: Furosemide therapy, even with nonconsistent dosing, was associated with an increased risk of bone fractures in children with congenital heart disease.

Determinants of Diuretic Responsiveness and Associated Outcomes During Acute Heart Failure Hospitalization: An Analysis From the NHLBI Heart Failure Network Clinical Trials.

BACKGROUND: Poor response to loop diuretic therapy is a marker of risk during heart failure hospitalization. We sought to describe baseline determinants of diuretic response and to further explore the relationship between this response and clinical outcomes. METHODS AND RESULTS: Patient data from the National Heart, Lung, and Blood Institute Heart Failure Network ROSE-AHF and CARRESS-HF clinical trials were analyzed to determine baseline determinants of diuretic response. Diuretic efficiency (DE) was defined as total 72-hour fluid output per total equivalent loop diuretic dose. Data from DOSE-AHF was then used to determine if these predictors of DE correlated with response to a high- versus low-dose diuretic strategy. At 72 hours, the high-DE group had median fluid output of 9071 ml (interquartile range: 7240-11775) with median furosemide dose of 320 mg (220-480) compared with 8030 ml (6300-9915) and 840 mg (600-1215) respectively for the low DE group. Cystatin C was independently associated with DE (odds ratio 0.36 per 1mg/L increase; 95% confidence interval: 0.24-0.56; P < 0.001). Independently from baseline characteristics, reduced fluid output, weight loss and DE were each associated with increased 60 day mortality. Among patients with estimated glomerular filtration rate below the median, those randomized to a high-dose strategy had improved symptoms compared with those randomized to a low-dose strategy. CONCLUSIONS: Elevated baseline cystatin C, as a biomarker of renal dysfunction, is associated with reduced diuretic response during heart failure hospitalization. Higher loop diuretic doses are required for therapeutic decongestion in patients with renal insufficiency. Poor response identifies a high-risk population.