Heart Failure Clinical Trials
Resume:
Citation: Wu, L.; Rodriguez, M.; El
Hachem, K.; Krittanawong, C.
Diuretic Treatment in Heart Failure: A
Practical Guide for Clinicians. J. Clin.
Med. 2024, 13, 4470. https://doi.org/
10.3390/jcm13154470
Academic Editor: Francesco Pelliccia
Received: 9 July 2024
Revised: 25 July 2024
Accepted: 26 July 2024
Published: 30 July 2024
Copyright: © 2024 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
conditions of the Creative Commons
Attribution (CC BY) license (https://
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4.0/).
Journal of
Clinical Medicine
Review
Diuretic Treatment in Heart Failure: A Practical Guide for Clinicians
Lingling Wu 1, Mario Rodriguez 2, Karim El Hachem 3 and Chayakrit Krittanawong 4,* 1 Cardiovascular Division, University of Alabama at Birmingham, Birmingham, AL 35294, USA 2 John T. Milliken Department of Medicine, Division of Cardiovascular Disease, Section of Advanced Heart Failure and Transplant, Barnes-Jewish Hospital, Washington University in St. Louis School of Medicine, St. Louis, MO 63110, USA
3 Division of Nephrology, Icahn School of Medicine at Mount Sinai, Mount Sinai Hospital, New York, NY 10029, USA
4 Section of Cardiology, Cardiology Division, NYU Langone Health and NYU School of Medicine, 550 First Avenue, New York, NY 10016, USA
* Correspondence: *********.************@**.***
Abstract: Congestion and fluid retention are the hallmarks of decompensated heart failure and the major reason for the hospitalization of patients with heart failure. Diuretics have been used in heart failure for decades, and they remain the backbone of the contemporary management of heart failure. Loop diuretics is the preferred diuretic, and it has been given a class I recommendation by clinical guidelines for the relief of congestion symptoms. Although loop diuretics have been used virtually among all patients with acute decompensated heart failure, there is still very limited clinical evidence to guide the optimized diuretics use. This is a sharp contrast to the rapidly growing evidence of the rest of the guideline-directed medical therapy of heart failure and calls for further studies. The loop diuretics possess a unique pharmacology and pharmacokinetics that lay the ground for different strategies to increase diuretic efficiency. However, many of these approaches have not been evaluated in randomized clinical trials. In recent years, a stepped and protocolized diuretics dosing has been suggested to have superior benefits over an individual clinician-based strategy. Diuretic resistance has been a major challenge to decongestion therapy for patients with heart failure and is associated with a poor clinical prognosis. Recently, therapy options have emerged to help overcome diuretic resistance to loop diuretics and have been evaluated in randomized clinical trials. In this review, we aim to provide a comprehensive review of the pharmacology and clinical use of loop diuretics in the context of heart failure, with attention to its side effects, and adjuncts, as well as the challenges and future direction.
Keywords: diuretic; heart failure
1. Introduction
Congestion and fluid retention are the hallmarks of decompensated heart failure (HF) and the major reason for the hospitalization of patients with heart failure [1]. Diuretics have been used in heart failure for decades, and they remain the backbone of the contemporary management of heart failure. Loop diuretics is the preferred diuretic, and it has been given a class I recommendation by clinical guidelines for the relief of congestion symptoms [2,3]. Although loop diuretics have been used virtually among all patients with acute decom- pensated heart failure, there is still very limited clinical evidence to guide the optimized diuretics use [4]. This is a sharp contrast to the rapidly growing evidence of the rest of the guideline-directed medical therapy of heart failure and calls for further studies. The loop diuretics possess a unique pharmacology and pharmacokinetics that lay the ground for different strategies to increase diuretic efficiency. However, many of these approaches have not been evaluated in randomized clinical trials (RCTs). In recent years, a stepped J. Clin. Med. 2024, 13, 4470. https://doi.org/10.3390/jcm13154470 https://www.mdpi.com/journal/jcm J. Clin. Med. 2024, 13, 4470 2 of 30
and protocolized diuretics dosing has been suggested to have superior benefits over an individual clinician-based strategy [5]. Diuretic resistance has been a major challenge to decongestion therapy for patients with heart failure and is associated with poor clinical prognosis [6]. Recently, therapy options have emerged to help overcome diuretic resistance to loop diuretics and have been evaluated in randomized clinical trials. In this narrative review, we aim to provide a comprehensive review of the pharmacology and clinical use of loop diuretics in the context of heart failure, with attention to its side effects, and adjuncts, as well as the challenges and future direction. A literature review was conducted through a search of MEDLINE and EMBASE databases using the following keywords: “heart failure; diuretics; clinical trial; review; meta-analysis; guideline” until 30 June 2024. Excluded were studies with only abstracts available or studies that focused on diuretics use among patients with hypertension only.
2. Loop Diuretics—Pharmacology
The kidney plays a vital role in maintaining the fluid and electrolyte balance in the body. Heart failure alternates the physiological process of renal filtration and reabsorption and triggers the maladaptation of the kidney through the activation of the neurohormone system [7]. These neurohormones often enhance the reabsorption of sodium and water to increase the preload of the left ventricle but also increase fluid retention and contribute to congestion symptoms [7]. Loop diuretics are the most potent diuretics and are the preferred agent in congestive heart failure [2,3]. Loop diuretics reversibly and competitively inhibit sodium-potassium-chloride cotransporter-2 (NKCC2) on the luminal side of the thick ascending loops’ epithelial cell, which accounts for 25–30% of the reabsorption of filtered NaCl from glomerular membranes [8]. As a result, the reabsorption of sodium and chloride declines, and tubular fluid becomes more hypertonic, which diminishes the osmotic gradient required for water reabsorption [8]. Loop diuretics also act on the NKCC1 cotransporter, which is expressed in vascular smooth muscle cells, and explain its vasodilatory effect [9]. Lastly, loop diuretics uniquely act on the distal part of the loop of Henle, which contains macula densa where the NKCC2 co-transporter is also expressed [10]. The inhibition of the NKCC2 co-transporter results in decreased sodium sensing from macula densa and promotes renin–angiotensin–aldosterone activation and sodium/water reabsorption in the proximal and distal tubule [11]. This compensatory hormonal response acts as a natural counterbalance to loop diuretics and contributes to diuretic resistance [12]. When loop diuretics are given to a patient who is naïve to diuretics, the hormonal response will not be sufficient compared to the overwhelmingly increased delivery of sodium to the distal tubule. Thus, the diuretic response is often robust. In comparison, distal tubule hypertrophy is frequently observed among patients on chronic loop diuretics. Therefore, the diuretic response is more blunted in such patients [13]. 3. Loop Diuretic Pharmacokinetics
Different loop diuretics possess different pharmacological properties and pharmacoki- netics. When given orally, loop diuretics are absorbed from the gastrointestinal tract and have various amounts of bioavailability depending on the agent. Furosemide has an unpre- dictable absorption and, on average, a lower bioavailability of 50%, whereas torsemide and bumetanide have a more predictable absorption and a high bioavailability (>80%) [14]. In the face of severe venous congestion and gut edema during acute decompensated heart failure, the intestinal absorption for loop diuretic can be further slowed, hence often requir- ing intravenous administration [15]. The exception is torsemide, which typically does not come in intravenous form and is better absorbed from the gastrointestinal tract compared to the rest of the loop diuretics [16]. When administrated intravenously, loop diuretics have a much faster onset, typically within 10 min versus 30 min to 1 h when taken orally [17]. Loop diuretics are highly bonded by albumin and will be transported to the kidney via blood flow, where it gains access to the tubular fluid by active proximal secretion via organic anion transporters (OATs) on the basolateral membrane and multidrug resistance- J. Clin. Med. 2024, 13, 4470 3 of 30
associated protein 4 (MRP4) on the luminal membrane of the proximal tubule [18]. Defects in tubular function, increased plasma organic anions such as the uremic anion, concomitant non-steroidal anti-inflammatory drug (NSAID) use, or hypoalbuminemia can negatively affect the active secretion process and delivery of the loop diuretics to thick ascending limb tubules [19]. The half-life of furosemide is about 1.5–2 h, whereas the half-life of bumetanide is shorter at 1 h, and that of torsemide is longer at 3–4 h [20]. Due to their shorter half-life, furosemide and bumetanide typically require at least a twice-a-day dosing schedule, whereas torsemide can be given once daily. The metabolism process also differs between loop diuretics. Torsemide and bumetanide are primarily metabolized through the liver, with lesser amounts through the kidney. In contrast, furosemide is primarily metabolized through glucuronidation in the kidney and, therefore, has a longer half-life in kidney failure [17].
Loop diuretics have a sigmoid-shaped dose–response curve which means the loop diuretics have a very minimal effect before reaching the threshold dose, beyond which point the loop diuretics rapidly approach the maximum effect with a dose increase, often termed the “ceiling effect” [19,21]. However, an increased diuretics dose above the ceiling dose will still produce more natriuresis because it will allow serum concentrations to be higher above the threshold dose for a longer time [20]. The pharmacokinetics features of loop diuretics underscore the recommendation of doubling the dose of the diuretic when resistance is met, as the dose–response curve is not linear but logarithmic. The dose–response curve is often shifted rightwards and downwards in acute decompensated heart failure, which increases the threshold dose and lowers the ceiling dose due to the attenuated natriuretic response to loop diuretics [22]. The continuous infusion of loop diuretics is theorized to have a better diuretic response and fewer side effects due to more stable serum concentrations above the threshold for a longer period compared to bolus administration. However, this has not been proven in the prospective clinical study [23]. The individual response to a fixed dose of diuretics varies and is often impacted by many factors contributing to diuretic resistance (discussed later). To describe the clinical response of heart failure patients to diuretics doses, the term “diuretics efficiency”, which is typically defined as net fluid loss per 40 mg of furosemide, has been used in recent years in clinical trials as an important clinical outcome in evaluating different diuretic strategies [24,25]. The variability of the threshold dose and response to diuretics among patients with heart failure also calls for a stepwise diuretic strategy, which will be discussed below. 4. Loop Diuretic Use in Acute Decompensated Heart Failure Congestion plays a central role in the pathogenesis of decompensated heart failure and contributes to the majority of the symptoms and hospitalization from heart failure [26]. Loop diuretics are the cornerstone of decongestion and have been recommended by clinical guidelines as the first-line therapy in congestive heart failure [2,3]. Despite its wide use, the clinical evidence of how to achieve decongestion effectively and safely remained limited. The DOSE trial evaluated intermittent vs. continuous IV loop diuretics and low- dose (IV equivalent of oral home dose) vs. high-dose (2.5 home dose) loop diuretics among patients with acute decompensated heart failure and found that, although there was no difference in the primary outcome (global assessment of symptoms and change in creatinine) at 72 h, it did show that high-dose loop diuretics was associated with a greater relief of dyspnea, weight loss, and net fluid loss [23] (Table 1). In the CARRESS-HF trial, a stepped pharmacological approach (urine-output-based) of diuretics was compared against ultrafiltration in acute decompensated heart failure. The stepped pharmacologic therapy algorithm of diuretics was found to be superior to ultrafiltration (UF) for the preservation of renal function at 96 h, with a similar amount of weight loss [5]. A post hoc analysis of the CARRESS-HF trial (stepped and protocolized approach) against the DOSE and ROSE-AHF trial (non-protocolized and clinicians-directed approach) revealed that a stepped diuretics dose strategy is associated with a greater net fluid and weight loss without being associated with renal compromise [27]. The urine output or net-fluid-based algorithm of diuretics J. Clin. Med. 2024, 13, 4470 4 of 30
dosing can be challenging due to inaccuracies and delays in data collection, thus limiting the ability to detect non-responders early. A natriuresis-based assessment has recently been suggested to overcome the limitation of the net-fluid-based assessment of the diuretic response [28]. Spot urine (first voided urine) sodium of less than 50–65 mEq/L was found to be associated with an inadequate diuretic response and adverse clinical outcomes [29,30]. A recent trial using protocolized natriuresis-guided decongestion (ENACT-HF trial) has been shown to be associated with a better urine output and shorter length of stay among patients with heart failure [31].
Based on emerging clinical evidence, a stepwise approach for the titration of diuretics in decompensated heart failure using a urine output and natriuresis-based approach has been proposed by ESC (Figure 1) [2]. Loop diuretics should be administered intravenously, and the starting dose for diuretics-naïve patients should be at least 20–40 mg and 1–2 times the total oral home dose diuretics for those already on home diuretics. After the first dose of diuretics, urine should be collected, and the total output should be measured. If the spot urine sodium is less than 50–70 mEq/L or urine output is less than 100 mL/h at 6 h, the loop diuretics dose should be doubled until the appropriate response or maximum dose (total daily dose of 400–600 mg furosemide or equivalent dose of loop diuretics) is reached, at which point an every 8 to 12 h dosing schedule can be applied and continued until decongestion. For those with persistent congestion with a urine output of less than 3–4 L in 24 h with a high dose or maximized loop diuretics dosing, further adjuncts of loop diuretics such as thiazide (first line), acetazolamide, or the sodium-glucose transport protein 2 (SGLT-2) inhibitor should be utilized. Ultrafiltration (UF) and advanced heart failure therapy should also be considered if the above strategy fails, and are generally associated with worse clinical outcome [6]. Loop diuretics administration can cause neuro- hormone activation, which is detrimental to acute heart failure [32]. Therefore, diuretics should not be given alone without the continuation/early initiation of other neurohormone modulators, such as Angiotensin receptor neprilysin inhibitor (ARNI), mineralocorticoid receptor antagonists (MRAs), beta-blockers (BBs), and SGLT-2-inhibitors. Once euvolemia is reached, an assessment should be made for the long-term diuretic needs, and a transition to oral diuretics should be planned. Clinical guidelines recommend transitioning to an oral diuretics dose at the lowest dose possible to avoid congestion [2]. There is no consensus about the dosing strategy for transitioning from intravenous to oral diuretics. For those already on home diuretics, a retrospective study has shown that an increase in the loop diuretic dose from the prehospitalization dose at discharge was associated with fewer 30-day readmissions [33]. It has also been suggested by guidelines that patients should be observed in the hospital for 24 h on oral diuretics before discharge [2]. However, this has been challenged by recent studies that failed to show any significant benefit with this approach [34,35].
J. Clin. Med. 2024, 13, 4470 5 of 30
Table 1. Summary of clinical trials or landmark studies for diuretics. Trials Intervention/Medication Patient Population Outcome Measured Conclusions DOES
(2 2 factorial design)
• Intravenous bolus versus
continuous infusion of furosemide;
• Low dose (1 oral dose) versus
high dose (2.5 oral dose)
of furosemide.
• Acute decompensated
heart failure;
• N = 308;
• Mean ejection fraction (EF) = 35%.
• Primary outcome: Global
symptom relief by visual analog
scale (VAS) area under the curve
(AUC); renal function;
• Secondary outcome: Change in
weight; net fluid loss;
decongestion; death,
rehospitalization,
emergency room visit.
• No difference in symptom relief or
changes in creatine between
intravenous bolus versus continuous
infusion or low dose versus high dose
of furosemide;
• High-dose furosemide was associated
with greater net fluid loss, weight loss
and improvement in dyspnea
compared to low-dose furosemide.
CARRESS-HF
Slow continuous ultrafiltration versus
stepped pharmacological treatment of
loop diuretics.
• Acute decompensated heart failure
(ADHF) with worsened renal
function (increase of Cr more than
0.3 mg/dL), with persistent
congestion despite
intravenous diuresis;
• N = 188;
• Median EF = 33%.
• Primary outcome: Change in
serum creatinine (Cr) and change
in weight between randomization
and 96 h;
• Secondary outcome: Rate of
clinical decongestion, global
well-being, and dyspnea
• Slow continuous ultrafiltration was
associated with a worsening primary
endpoint (driven by worsening serum
Cr) compared to stepped
pharmacological treatment;
• Similar rate of weight loss
and decongestion.
ENACT-HF Protocolized natriuresis-based diuretics
dosing versus standard of care.
• Acute decompensated heart
failure;
• N = 401;
• EF: 55% of patients had EF < 40%.
• Primary outcome: Natriuresis after
24 h;
• Secondary outcome: Diuresis,
weight loss, change in congestion
score and length of stay.
• Protocol-driven and natriuresis-based
diuresis was associated with higher
natriuresis, higher urine output, and
shorter length of stay;
• There was no difference in motility
between the two arms.
Transform HF Torsemide versus furosemide.
• Discharged patient with
decompensated heart failure;
• N = 2859;
• EF: 64% of patients had EF <= 40%.
• Primary outcome:
All-cause mortality;
• Secondary outcome: All-cause
mortality or hospitalization;
quality of life.
• No difference in all-cause mortality in
one year;
• No difference between groups for the
composite of all-cause mortality or
all-cause hospitalization at 12 months;
• No difference in quality of life
between the two groups.
J. Clin. Med. 2024, 13, 4470 6 of 30
Table 1. Cont.
Trials Intervention/Medication Patient Population Outcome Measured Conclusions 3T Trial
Oral metolazone, intravenous
chlorothiazide, or tolvaptan therapy in
addition to loop diuretics.
• Acute decompensated heart failure
with diuretic resistance
(furosemide equivalent dosage of
>=240 mg/day with persistent
congestion);
• N = 60;
• Mean EF = 30%.
• Primary outcome: 48 h
weight loss;
• Secondary outcome: 48 h total and
net urine output; congestion
symptoms; diuretic efficiency.
• Among patients with loop diuretic
resistance, the addition of oral
metolazone, intravenous
chlorothiazide, or tolvaptan therapy
all resulted in significant weight
reduction;
• There was no between-group
difference in the primary outcome.
CLOROTIC Hydrochlorothiazide versus placebo, in
addition to intravenous loop diuretics.
• Acute decompensated
heart failure;
• N = 230;
• Mean EF = 56%.
• Primary outcome: Changes in
body weight and patient-reported
dyspnea 72 h after randomization;
• Secondary outcome:
Diuretic response;
mortality/rehospitalizations at
30 and 90 days.
• Hydrochlorothiazide, in addition to
intravenous loop diuretics, was
associated with greater weight loss at
72 h;
• There was no difference in relief of
dyspnea between the two groups;
• Hydrochlorothiazide was associated
with improved diuretic efficiency but
more frequent worsening of
renal function.
EMPAG-HF
Early initiation (day one of
hospitalization) of empagliflozin versus
placebo in addition to standard medical
treatment of acute decompensated
heart failure.
• Acute decompensated
heart failure;
• N = 60;
• Mean EF = 45%.
• Primary outcome: Total urine
output measured and summed
over 5 days;
• Secondary outcome:
Renal function.
• Use of empagliflozin 25 mg within
12 h of hospitalized ADHF patients
was associated with a 25% increase in
cumulative urine output in 5 days;
• Empagliflozin use was associated with
a larger decrease in N-terminal-pro
B-type natriuretic peptide
(NT-proBNP) levels and improved
NYHA class with a better eGFR at day
30 compared to placebo.
J. Clin. Med. 2024, 13, 4470 7 of 30
Table 1. Cont.
Trials Intervention/Medication Patient Population Outcome Measured Conclusions EMPULSE
Empagliflozin versus placebo, in
addition to standard medical treatment
of acute decompensated heart failure.
• Acute decompensated
heart failure;
• N = 530;
• Median EF = 32%.
• Primary outcome: Composite of
death, number of heart failure
events, time to first heart failure
event, and change in Kansas City
Cardiomyopathy
Questionnaire-Total Symptom
Score (KCCQ-TSS) from baseline
to 90 days;
• Secondary outcome: Acute renal
failure; body weight change.
• Empagliflozin was associated with
significant clinical benefits of primary
outcome (time to death, heart failure
events, improvement of total
symptoms score) after 90 days
of treatment;
• Empagliflozin was also associated
with greater weight loss changes in
congestion score compared to placebo.
DAPA-RESIST Dapagliflozin versus metolazone for
heart failure with diuretic resistance.
• Acute decompensated heart failure
with diuretic resistance (receiving
160 mg IV furosemide in 24 h
with insufficient decongestion);
• N = 61;
• Median EF = 45%.
• Primary outcome: Diuretic effect
(weight changes) from
randomization to 96 h;
• Secondary outcome: Change in
congestion; loop
diuretic efficiency.
• There was no difference in weight
changes at 96 h between dapagliflozin
and metolazone;
• Dapagliflozin groups had higher
cumulative loop diuretic dosing
requirements but were associated with
less hypokalemia, hypotension, and
worsening creatines.
DICTATE-AHF
Early initiation of dapagliflozin versus
placebo in addition to standard medical
treatment of acute decompensated
heart failure.
• Acute decompensated
heart failure;
• N = 240;
• EF: 52% had EF <= 40%.
• Primary outcome: Diuretic
efficiency defined as cumulative
weight change per cumulative
loop diuretic dose;
• Secondary outcome: 24 h
natriuresis and urine output.
• Dapagliflozin was not associated with
a statistically significant reduction in
weight-based diuretic efficiency
(p = 0.06);
• Dapagliflozin was associated with
increased natriuresis (p = 0.03) and
urine output (p = 0.005) at 24 h;
• Early initiation of Dapagliflozin was
not associated with an increase in any
safety events.
J. Clin. Med. 2024, 13, 4470 8 of 30
Table 1. Cont.
Trials Intervention/Medication Patient Population Outcome Measured Conclusions ADVOR
Intravenous administration of
acetazolamide (500 mg daily) versus
placebo in addition to standardized
intravenous loop diuretics.
• Acute decompensated
heart failure;
• N = 519;
• Mean EF = 43%;
• Patient on SGLT-2 inhibitors
were excluded.
• Primary outcome: Successful
decongestion within 72 h;
• Secondary outcome: composite
end point of death from any cause
or rehospitalization for heart
failure during three months of
follow-up; length of stay.
• Acetazolamide was associated with a
higher incidence of successful
decongestion at 72 h;
• There was no difference in all-cause
mortality and heart failure;
• Acetazolamide was associated with
shorter length of stay.
ATHENA-HF
High-dose spironolactone versus
low-dose or placebo for acute
decompensated heart failure patient.
• Acute decompensated
heart failure;
• N= 360;
• Median EF = 34%.
• Primary outcome: change in
NT-proBNP levels;
• Secondary outcome: clinical
congestion score; dyspnea
assessment; net urine output; and
net weight change.
• High-dose spironolactone in ADHF
was not associated with improvement
in NT proBNP levels;
• There was also no difference in
secondary outcome, including clinical
congestion score, net urine out, or net
weight change.
ROSE HF
Low-dose dopamine (2 µg/kg/min) or
low-dose nesiritide (0.005 µg/kg/min
without bolus) in addition to
standard diuresis.
• Acute decompensated heart failure
with renal dysfunction;
• N = 360;
• Median EF = 33%.
• Primary outcome: 72 h cumulative
urine volume (decongestion
endpoint); change in serum
cystatin C from enrollment to 72 h
(renal endpoint);
• Secondary outcome: change in
creatine; dyspnea assessment,
changes in weight, worsening
heart failure, death, heart
failure rehospitalization.
• There was no difference in cumulative
urine volume or changes in serum
cystatin outcome between low-dose
dopamine, low-dose nesiritide,
and placebo;
• There was no difference in death HF
hospitalization at 60 days
between groups;
• Patients with ejection fraction 50%
appeared to derive more benefit from
dopamine (p for interaction = 0.01).
J. Clin. Med. 2024, 13, 4470 9 of 30
Table 1. Cont.
Trials Intervention/Medication Patient Population Outcome Measured Conclusions OPTIME-CHF Short-term use of milrinone versus
placebo in addition to standard therapy.
• Acute decompensated heart failure
not requiring inotropes supports;
• N = 951;
• Mean EF = 23%.
• Primary outcome: Cumulative
days of hospitalization within
60 days after randomization;
• Secondary outcome: Treatment
failure caused by progression
heart failure or adverse effect;
hypotension; arrythmia.
• The primary endpoint of
cardiovascular hospital days at
60 days was not significantly different
between milrinone and
placebo groups;
• Sustained hypotension and new atrial
fibrillation or flutter were more
common for milrinone than
placebo subjects.
CHAMPION
Implantable pulmonary artery pressure
monitors to guide the medical
management of patients with heart
failure.
• NYHA class III heart failure
symptoms and recent
hospitalization for heart failure;
• N = 2859;
• EF: 83% of patients had EF <= 40%.
• Primary outcome: Rate of heart
failure-related hospitalizations at
six months;
• Secondary outcome: Change from
baseline in pulmonary artery
mean pressure, Minnesota Living
with Heart Failure Questionnaire
at six months; device complication.
• The use of implantable pulmonary
artery pressure monitors was
associated with a significant reduction
in HF hospitalization at six months;
• The effect of implantable pulmonary
artery pressure monitors was durable
at 18 months;
• Overall freedom from device-related
complications was 98.6%.
J. Clin. Med. 2024, 13, 4470 10 of 30
Figure 1. Algorithm stepwise approaches for how to use diuretics in ADHF (adapted from 2021 ESC HF guideline).
J. Clin. Med. 2024, 13, 4470 11 of 30
5. Loop Diuretic Use in Chronic Congestive Heart Failure Diuretics are recommended by clinical guidelines for chronic congestive heart failure patients to prevent symptoms from congestion [2,3]. Furosemide is the most used agent due to its vast clinical experience and availability [36]. Some clinicians favor torsemide and bumetanide due to their better bioavailability and/(or) longer half-life. Early studies have suggested that torsemide might be superior to furosemide [37,38]. This was investi- gated in a recent Transform HF trial, which failed to demonstrate the benefit of torsemide over furosemide for all-cause mortality over 12 months [39]. Current clinical guidelines recommend using the lowest possible maintenance diuretic dose for chronic heart failure patients, as diuretics can be associated with side effects, including volume depletion and electrolyte derangement [3]. The dose of diuretics often changes over time, as it is shown in the CHAMPION trial [40]. Therefore, it is important to monitor and schedule regular follow-up visits after the discharge from acute hospitalization. An improved hemody- namical profile and lowered dose requirement of diuretics was observed frequently in heart failure patients after the initiation of guideline-directed medical therapy [41]. An observational study suggests chronic congestive heart failure patients without diuretics requirement have a better prognosis than those who require diuretics [42]. The chronic use of diuretics can also cause side effects such as electrolyte derangement and hypovolemia. Therefore, the active down-titration of diuretics has been suggested to be beneficial for chronic heart failure patients. A recent trial that enrolled 417 stable heart failure patients on low-dose diuretics showed that the withdrawal of diuretics in the
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