Acute heart failure (AHF) is the most common hospital discharge diagnosis among Medicare beneficiaries resulting in approximately one million hospitalizations annually and contributing to an additional two million hospitalizations as a secondary diagnosis [1]. Congestion is the main reason for admission of these patients, with loop diuretics as the cornerstone of therapy [2]. However, the therapeutic response is known to be variable, with a significant subset of patients developing diuretic resistance (DR), qualitatively defined as an inadequate rate/quantity of natriuresis despite an optimal diuretic regimen [3]. The clinical hallmarks of loop DR are inadequate relief of congestion, increased risk of in-hospital worsening of heart failure, and a significant increase in rehospitalization rates. The clinicians’ war on DR in AHF has so far been on two fronts; how to reliably predict it before it settles, and how to manage it efficiently when it is already there.

Using spot urine sodium to predict the response to loop diuretics is the foundation of all prediction models. The furosemide stress test (FST), originally developed for patients with acute kidney injury in the intensive care unit to predict progression of the kidney disease, has been tested in patients with AHF [4]. The preliminary results suggest that FST (1-time intravenous dose of 1.0 or 1.5 mg/kg depending on prior furosemide exposure) may also have a role in this setting by identifying those patients at risk of an inadequate response [5]. Similarly, there has been an increasing interest in using timed urine collection to guide diuretic dosing. A low urine sodium (<50–70 mmol/L, 1–2 h after administration of an intravenous loop diuretic) has been considered inadequate, indicating the need for doubling of the dose until adequate natriuresis is achieved [3]. Additional studies are underway to gather more data on the value of natriuresis-guided approach to AHF management (Table 1). A natriuretic equation/calculator has also been proposed recently that uses a spot urine sample to predict the 6-h cumulative sodium excretion [6]. This information can then be used to guide therapy of AHF.

Table 1.

Ongoing studies examining natriuresis-guided therapy in acute heart failure

NameClinical trial identifierExpected patients, nDesignIntervention armControl armPrimary endpointEstimated completion date
PUSH-HF NCT04606927 310 RCT Natriuresis-guided treatment Standard of care Total natriuresis after 24 h, first occurrence of all-cause mortality or heart failure rehospitalization Jun 2023 
DECONGEST NCT05411991 104 RCT Natriuresis-guided treatment1 Standard of care Mortality, days in hospital, and decongestion Jul 2023 
ENACT-HF NR2 454 Multinational pragmatic Natriuresis-guided treatment None Total natriuresis after 24 h NR 
Collins S, et al.3 NCT04481919 484 RCT Natriuresis-guided treatment Guideline-based care Days of clinical benefit (global clinical status, hospital days, and death) Dec 2026 
NameClinical trial identifierExpected patients, nDesignIntervention armControl armPrimary endpointEstimated completion date
PUSH-HF NCT04606927 310 RCT Natriuresis-guided treatment Standard of care Total natriuresis after 24 h, first occurrence of all-cause mortality or heart failure rehospitalization Jun 2023 
DECONGEST NCT05411991 104 RCT Natriuresis-guided treatment1 Standard of care Mortality, days in hospital, and decongestion Jul 2023 
ENACT-HF NR2 454 Multinational pragmatic Natriuresis-guided treatment None Total natriuresis after 24 h NR 
Collins S, et al.3 NCT04481919 484 RCT Natriuresis-guided treatment Guideline-based care Days of clinical benefit (global clinical status, hospital days, and death) Dec 2026 

DECONGEST, Diuretic Treatment in Acute Heart Failure with Volume Overload Guided by Serial Spot Urine Sodium Assessment; ENACT-HF, efficacy of a standardized diuretic protocol in acute heart failure; PUSH-HF, Pragmatic Urinary Sodium-based Treatment algoritHm in Acute Heart Failure; RCT, randomized controlled trial; NR, not reported.

1Upfront use of acetazolamide and chlorthalidone. Canrenoate is added if diuretic resistance (full nephron blockade).

2Dauw J, et al. ESC Heart Fail 2021;8:4885–4692.

3A Randomized Trial of Protocolized Diuretic Therapy Compared to Standard Care in Emergency Department Patients With Acute Heart Failure. www.ClinicalTrials.gov access date: February 25, 2023.

In parallel with attempts to identify a practical and reliable method for prediction of DR, a number of studies have been carried out to identify an optimal management strategy. Several non-diuretic approaches have been explored such as low-dose nesiritide, low-dose dopamine, and hypertonic saline. In general, the results have been negative or need validation by larger trials. The choice of the loop agent has been another consideration. While furosemide is often used in this setting, torsemide has long been suspected to be superior due to its increased bioavailability, a longer half-life, and added benefits related to aldosterone production and ventricular remodeling [7]. However, a few months ago, a large pragmatic randomized trial (Torsemide Comparison with Furosemide for Management of Heart Failure – TRANSFORM-HF) convincingly showed that torsemide has no advantage over furosemide in terms of the impact on survival or rehospitalization among patients with AHF [8].

Without an identifiable difference between available agents, our attention would shift back to the regimens in which these medications are incorporated. Which one is an advantageous strategy: maximizing the dose of a loop diuretic, or using an add-on agent for combination diuretic therapy (CDT)? No study has so far addressed this question, but most experts recommend delaying CDT until the loop diuretic dose is maximized [9]. There is, however, no consensus on the magnitude of titration that is appropriate. In the landmark Diuretic Strategies in Patients with Acute Decompensated Heart Failure (DOSE) trial, high-dose furosemide (2.5 times the maintenance dose) was associated with improvement in net fluid loss, more pronounced weight loss, and faster symptom relief [10]. The results implied that an aggressive approach to loop diuretic dosing should generally be preferred in AHF. Over the last few months, the results of two large, randomized trials of CDT were published, which regenerated the interest in this strategy. Acetazolamide in Acute Decompensated Heart Failure with Volume Overload (ADVOR) tried acetazolamide as the add-on agent and reported a greater incidence of successful decongestion [11]. In a prespecified analysis, the investigators showed that allocation to acetazolamide strongly and independently predicted enhanced natriuresis, which in turn was associated with more successful relief of congestion and shorter length of stay [12]. Similarly, in combining loop with thiazide diuretics for decompensated heart failure (CLOROTIC), addition of hydrochlorothiazide to loop diuretic therapy resulted in improved diuretic response as compared with placebo [13]. While sequential nephron blockade remains the most common strategy to overcome DR, the impact is generally modest (less than 50% increase in natriuresis) [9]. Interestingly, the vast majority of the landmark studies exploring the role of CDT in AHF, including the two most recent ones, have used the add-on diuretic within 24 h of hospital admission for all patients regardless of how they responded to loop diuretics [11]. The 3T trial is different in that it compared metolazone, intravenous chlorothiazide, and tolvaptan only if AHF patients presented with DR [14]. The authors reported adequate diuresis for all three medications but did not observe any between-group differences for the add-on agents. Notably, not only have the studies so far failed to show a salutary impact on survival for CDT, but there has also been a notion that, compared with high-dose loop diuretics, addition of metolazone may be associated with increased mortality [15].

Considering our armamentarium summarized above, the war on DR is clearly not going to be over soon. The prediction modeling of DR is still in its infancy and needs much scrutiny before becoming a widely applied tool. Use of timed urine collection outside of an intensive care setting may prove challenging in most centers; none of the three landmark diuretic trials that were published over the past few months used natriuresis to guide their therapy [8]. Moreover, the current methods for prediction of DR have not yet been used in large-scale prospective studies, nor have they been explored in the real-world to assess the impact on outcomes. Whether artificial intelligence and machine learning models would change the landscape remains to be explored (Segar M, et al. abstract presented at the American Heart Association annual meeting 2022. Circulation 2022;146:A14862).

When it comes to management, the prospects are unfortunately not much brighter than predictability. In fact, the most robust “stepped” diuretic titration regimen that we have (which also includes CDT) was developed, almost fortuitously, when investigators were trying to design a control arm in a study of ultrafiltration for AHF [16]. Moreover, both ADVOR and CLOROTIC introduced the add-on agent as an upfront strategy rather than a rescue therapy to address DR, which is not in line with the current guidelines of the professional societies for CDT. Therefore, while helpful as a potential diuretic strategy in general, they do not offer a solution for management of DR.

The combined lack of a standardized approach for prediction and management of DR is a recipe for highly variable and potentially suboptimal care [17]. Many of the current diuretics have been available for several decades and the war against DR has also been going on for so long with the end still not being in sight. It is time to reconsider our approach and open a third front. Instead of waiting and advocating for more and more trials, we need to take a proactive strategy. A group of physicians with diverse clinical backgrounds should convene to examine the currently available data with the goal of generating reports on how to define and address DR. At this stage, we need more of an advisory group than experts; guidelines provide scientific basis and evidence, while the advisory group would offer practical recommendations on how to get it done. These recommendations will not need to be a road map for treatment of all AHF patients with DR, but rather deliberately designed to be practical and effective in the management of most individuals, while improving the care of all. They should emphasize simple diagnostic evaluation and detailed management algorithms while also recognizing diversity of resources. This will help maintain the relevance to non-heart failure physicians such as hospitalists who carry the burden of care so they perceive them as suitable for every patient in every hospital and not just in large medical centers. The current guidelines of professional societies are often generated based on data from resourceful academic centers that specialize in the care of complex patients. They ignore the inherent differences that exist among institutions, patients’ characteristics, and care settings (e.g., intravenous acetazolamide used in ADVOR is not available in some countries, and timed urine sodium generally requires higher acuity care units). Like consensus documents, not all members or experts would agree with each aspect of the recommendations, but they are reached by compromise and group decision-making. It should be recognized that ongoing studies would result in changes and, as this information becomes available, the report would be revisited, as such be evolutionary. Finally, it should be recognized that renal sodium avidity in general is a marker of more pronounced maladaptive neurohormonal activation and identifies a subset of patients at higher risk of untoward outcomes. Based on available data, elements of guideline-directed medical therapy can be safely initiated in the hospital in many of the patients admitted for AHF [18]. Some of these agents confer natriuretic properties (e.g., sodium-glucose contrasporter-2 inhibitors and neprilysin inhibitors) and may result in more efficient decongestion while also portending other benefits such as reducing mortality. Therefore, a discussion on optimal decongestive strategies in AHF would be more likely to enhance the outcomes beyond decongestion if proactive in-hospital guideline-directed medical therapy implementation and titration would be pursued simultaneously.

The author has received advisory/consultancy fees from the following: Baxter Inc., Elsevier Inc., Horizon Inc., Nuwellis Inc., and W.L.Gore Inc. that are not relevant to the content of this article.

No funding supported this manuscript.

Amir Kazory has been the sole author of this manuscript.

1.
Benjamin
EJ
,
Muntner
P
,
Alonso
A
,
Bittencourt
MS
,
Callaway
CW
,
Carson
AP
.
Heart disease and stroke statistics-2019 update: a report from the American heart association
.
Circulation
.
2019 Mar 5
139
10
e56
528
.
2.
Chioncel
O
,
Mebazaa
A
,
Harjola
V-P
,
Coats
AJ
,
Piepoli
MF
,
Crespo-Leiro
MG
.
Clinical phenotypes and outcome of patients hospitalized for acute heart failure: the ESC heart failure long-term registry
.
Eur J Heart Fail
.
2017 Oct
19
10
1242
54
.
3.
Cox
ZL
,
Rao
VS
,
Testani
JM
.
Classic and novel mechanisms of diuretic resistance in cardiorenal syndrome
.
Kidney360
.
2022 May 26
3
5
954
67
.
4.
Chawla
LS
,
Davison
DL
,
Brasha-Mitchell
E
,
Koyner
JL
,
Arthur
JM
,
Shaw
AD
.
Development and standardization of a furosemide stress test to predict the severity of acute kidney injury
.
Crit Care
.
2013 Sep 20
17
5
R207
.
5.
Caravaca Pérez
P
,
Nuche
J
,
Morán Fernández
L
,
Lora
D
,
Blázquez-Bermejo
Z
,
López-Azor
JC
.
Potential role of natriuretic response to furosemide stress test during acute heart failure
.
Circ Heart Fail
.
2021 Jun 15
14
6
e008166
.
6.
Testani
JM
,
Hanberg
JS
,
Cheng
S
,
Rao
V
,
Onyebeke
C
,
Laur
O
.
Rapid and highly accurate prediction of poor loop diuretic natriuretic response in patients with heart failure
.
Circ Heart Fail
.
2016 Jan
9
1
e002370
.
7.
Buggey
J
,
Mentz
RJ
,
Pitt
B
,
Eisenstein
EL
,
Anstrom
KJ
,
Velazquez
EJ
.
A reappraisal of loop diuretic choice in heart failure patients
.
Am Heart J
.
2015 Mar
169
3
323
33
.
8.
Mentz
RJ
,
Anstrom
KJ
,
Eisenstein
EL
,
Sapp
S
,
Greene
SJ
,
Morgan
S
.
Effect of Torsemide vs Furosemide After Discharge on All-Cause Mortality in Patients Hospitalized with Heart Failure: the TRANSFORM-HF randomized clinical trial
.
JAMA
.
2023 Jan 17
329
3
214
23
.
9.
Kazory
A
,
Ronco
C
.
Tackling congestion in acute heart failure; is it the primetime for “combo diuretic therapy”
.
Cardiorenal Med
.
2023 Feb 14
184
8
. Published ahead of Print.
10.
Felker
GM
,
Lee
KL
,
Bull
DA
,
Redfield
MM
,
Stevenson
LW
,
Goldsmith
SR
.
Diuretic strategies in patients with acute decompensated heart failure
.
N Engl J Med
.
2011 Mar 3
364
9
797
805
.
11.
Mullens
W
,
Dauw
J
,
Martens
P
,
Verbrugge
FH
,
Nijst
P
,
Meekers
E
.
Acetazolamide in acute decompensated heart failure with Volume Overload
.
N Engl J Med
.
2022 Sep 29
387
13
1185
95
.
12.
Verbrugge
FH
,
Martens
P
,
Dauw
J
,
Nijst
P
,
Meekers
E
,
Augusto
SN
Jr
.
Natriuretic response to acetazolamide in patients with acute heart failure and Volume Overload
.
J Am Coll Cardiol
.
2023 May 23
81
20
2013
24
.
13.
Trulls
JC
,
Morales-Rull
JL
,
Casado
J
,
Carrera-Izquierdo
M
,
Snchez-Marteles
M
,
Conde-Martel
A
.
Combining loop with thiazide diuretics for decompensated heart failure: the CLOROTIC trial
.
Eur Heart J
.
2023 Feb 1
44
5
411
21
.
14.
Cox
ZL
,
Hung
R
,
Lenihan
DJ
,
Testani
JM
.
Diuretic strategies for loop diuretic resistance in acute heart failure: the 3T trial
.
JACC Heart Fail
.
2020 Mar
8
3
157
68
.
15.
Brisco-Bacik
MA
,
Ter Maaten
JM
,
Houser
SR
,
Vedage
NA
,
Rao
V
,
Ahmad
T
.
Outcomes associated with a strategy of adjuvant metolazone or high-dose loop diuretics in acute decompensated heart failure: a propensity analysis
.
J Am Heart Assoc
.
2018 Sep 18
7
18
e009149
.
16.
Bart
BA
,
Goldsmith
SR
,
Lee
KL
,
Givertz
MM
,
O’Connor
CM
,
Bull
DA
.
Ultrafiltration in decompensated heart failure with cardiorenal syndrome
.
N Engl J Med
.
2012 Dec 13
367
24
2296
304
.
17.
Kazory
A
.
Combination diuretic therapy to counter renal sodium avidity in acute heart failure: trials and tribulations
.
Clin J Am Soc Nephrol
.
2023 Apr 27
. Published ahead of Print.
18.
Bhagat
AA
,
Greene
SJ
,
Vaduganathan
M
,
Fonarow
GC
,
Butler
J
.
Initiation, continuation, switching, and withdrawal of heart failure medical therapies during hospitalization
.
JACC Heart Fail
.
2019 Jan
7
1
1
12
.