Current Heart Failure Reports

https://doi.org/10.1007/s11897-024-00659-9

REVIEW

Combinational Diuretics in Heart Failure

Joan Carles Trullàs1,2 · Jesús Casado3 · Marta Cobo‑Marcos4 · Francesc Formiga5 · José Luís Morales‑Rull6 ·
Julio Núñez7,8,9,10 · Luís Manzano11

Accepted: 20 March 2024

© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2024

Abstract
Purpose of Review Diuretics are the cornerstone therapy for acute heart failure (HF) and congestion. Patients chronically
exposed to loop diuretics may develop diuretic resistance as a consequence of nephron remodelling, and the combination of
diuretics will be necessary to improve diuretic response and achieve decongestion. This review integrates data from recent
research and offers a practical approach to current pharmacologic therapies to manage congestion in HF with a focus on
combinational therapy.
Recent Findings Until recently, combined diuretic treatment was based on observational studies and expert opinion. Recent
evidence from clinical trials has shown that combined diuretic treatment can be started earlier without escalating the doses
of loop diuretics with an adequate safety profile.
Summary Diuretic combination is a promising strategy for overcoming diuretic resistance in HF. Further studies aiming to
get more insights into the pathophysiology of diuretic resistance and large clinical trials confirming the safety and efficacy
over standard diuretics regimens are warranted.

Keywords Heart failure · Diuretics · Furosemide · Thiazides · Acetazolamide · Spironolactone

6
* Joan Carles Trullàs Internal Medicine Department, Heart Failure Unit, Hospital
[email protected] Universitari Arnau de Villanova, Institut de Recerca
Biomédica (IRBLleida), Avinguda Alcalde Rovira Roure, 80,
1
Internal Medicine Department, Hospital d’Olot I Comarcal 25198 Lleida, Spain
de La Garrotxa, Avinguda Dels Països Catalans 86, 7
Cardiology Department, Hospital Clínico Universitario de
17800 Olot, Girona, Spain
Valencia, Valencia, Spain
2
Tissue Repair and Regeneration Laboratory (TR2Lab), 8
Instituto de Investigación Sanitaria INCLIVA, Valencia,
Institut de Recerca I Innovació en Ciències de La Vida I de
Spain
La Salut a La Catalunya Central (IrisCC), Ctra. de Roda, 70
9
08500 Vic, Barcelona, Spain Department of Medicine, University of Valencia, Valencia,
3 Spain
Internal Medicine Department, Hospital Universitario
10
de Getafe, Carretera de Madrid - Toledo, Km 12,500, Centro de Investigación Biomédica en Red - Cardiovascular
28905 Madrid, Spain (CIBER-CV), Madrid, Spain
4 11
Cardiology Department, Hospital Universitario Puerta de Internal Medicine Department, Hospital Universitario Ramón
Hierro Majadahonda (IDIPHISA), Centro de Investigación y Cajal, IRYCIS, Universidad de Alcalá, M‑607, 9, 100,
Biomédica en Red en Enfermedades Cardiovasculares 28034 Madrid, Spain
(CIBERCV), Madrid, Spain
5
Internal Medicine Department, Hospital Universitari
de Bellvitge, IDIBELL, Carrer de La Feixa Llarga S/N,
L’Hospitalet de Llobregat, 08907 Barcelona, Spain

Vol.:(0123456789)
 Current Heart Failure Reports

Introduction Furthermore, chronic diuretic treatment dramatically

increases the capacity of the distal nephron to reabsorb
The heart failure (HF) syndrome was described as an delivered sodium chloride (NaCl), leading to the second-
emerging epidemic about 25 years ago [1]. Today, HF ary decline in natriuresis (it is the so-called “braking
remains a serious clinical and public health problem as phenomenon”). Secondary increases in NaCl absorptive
the total number of patients living with HF is increas- capacity are associated with remarkable nephron remod-
ing, reflecting the chronic course of the disease as well elling, with hypertrophy of the distal convoluted tubule,
as population growth and ageing [1]. HF hospitaliza- connecting tubule, and collecting duct, which bypasses the
tions represent 1 to 2% of all hospital admissions, and proximal effect of the loop diuretic and results in enhanced
HF is the most common diagnosis in hospitalized patients sodium retention. These morphological and functional
aged > 65 years. HF survival has improved substantially in alterations, described almost four decades ago [10, 11],
the last decades but, unfortunately, remains prohibitively are the basis for the lack of diuretic efficacy in patients
high [1]. chronically treated with loop diuretics [8, 9, 12].
Over the past decades, a multitude of new therapies for Similar to the classification of acute kidney injury, an
the management of patients with HF have shown benefit, anatomically based categorization of the mechanisms of
especially for HF with reduced ejection fraction (HFrEF). diuretic resistance in HF has been proposed dichotomizing
The more recently updated clinical practice guidelines diuretic resistance in pre-renal and intrarenal. Pre-renal
emphasize the importance of early and rapid initiation of mechanisms appear to be proportionately less important in
guideline-directed medical therapies (GDMTs) that can patients with HF where intrarenal mechanisms dominate.
improve life expectancy [2, 3]. Intrarenal mechanisms are further divided based on the
More than 80% of patients with acute heart failure anatomic nephron segments in which the resistance mech-
(AHF) present with signs and symptoms of congestion, anism arises (pre-loop of Henle, loop of Henle, and post-
which is the main reason why these patients seek medical loop of Henle) (Fig. 1). Although most filtered sodium is
care [4]. Given this pivotal role of congestion in AHF, reabsorbed in the proximal tubule and loop of Henle, most
diuretics are still a cornerstone of therapy in AHF [5]. data from animal models and current human literature
In the early stages of HF, patients usually respond indicates that the post-loop of Henle tubular mechanisms
well to single-loop diuretic therapy. As the disease pro- (compensatory distal tubular sodium reabsorption) has the
gresses, other comorbidities appear, such as renal failure, greater contribution to diuretic resistance in HF [8, 13]. In
and patients are chronically exposed to loop diuretics, and this sense, a recent mechanistic study investigated the two
consequently, the diuretic efficiency decreases [6]. In our main mechanisms of diuretic resistance in HF (decreased
clinical practice, up to 20–30% of patients with HF treated tubular delivery of furosemide to its site of action and
with loop diuretics will require admission for decompensa- decreased tubular responsiveness) and compared chronic
tion and a combination of diuretics to improve the diuretic furosemide users vs. furosemide naïve patients [14•]. The
response and achieve decongestion [6, 7]. greater diuretic response in loop diuretic naïve patients
The aim of this review is to integrate data from recent was not due to better loop diuretic delivery to the nephron,
research and offer a practical approach to current pharma- as both groups had similar estimated glomerular filtra-
cologic therapies to manage congestion in HF, with a focus tion rate (eGFR)-adjusted cumulative furosemide urinary
on combinational therapy. excretion. Instead, the greater diuretic response in diu-
retic naïve patients was due to a better tubular response
to furosemide [14•]. These findings indicate that diuretic
resistance in chronic loop diuretic therapy is mainly driven
The Rationale for Combining Diuretics: by decreased tubular responsiveness rather than insuffi-
Diuretic Resistance and Pre‑emptive cient furosemide tubular delivery. Further studies aiming
Sequential Nephron Blockade to better elucidate the pathophysiology of diuretic resist-
ance would be necessary to personalize diuretic strategies
Poor response to diuretics is a crucial important clinical by adapting them to nephron remodelling.
problem in patients with AHF, and the underlying patho- More recently, there has been an increase in the interest
physiological mechanisms are diverse: impaired absorp- of sequential nephron blockade as a pre-emptive strategy
tion, decreased renal blood flow, azotaemia, hypoalbu- in patients with AHF. In this scenario, sequential nephron
minemia, and proteinuria (resulting in reduced levels of blockade has been applied in patients who were not demon-
active diuretics in the tubular lumen) might affect diuretic strably diuretic resistant, but instead, it has been used as an
effectiveness [8, 9]. approach to accelerating the relief of signs and symptoms
of congestion.
Current Heart Failure Reports

Fig. 1  Mechanisms of diuretic resistance

Combining Mineralocorticoid Receptor Combining Acetazolamide with Loop

Antagonists with Loop Diuretics Diuretics

Low-dose mineralocorticoid receptor antagonists (MRAs) The mechanism of action of acetazolamide is primarily
as neurohormonal antagonists are a well-established treat- through the inhibition of carbonic anhydrase, which leads
ment to improve survival in patients with HFrEF, but the to increased excretion of bicarbonate, sodium, and water
role of high-dose MRAs in AHF remains uncertain. Some in the urine, producing a diuretic effect [17]. Recently, the
studies have shown that high-dose MRAs may result in sig- ADVOR (Acetazolamide in Decompensated Heart Failure
nificant natriuresis and clinical improvement. For instance, a With Volume Overload) trial, a multicentre, randomized,
single-centre, single-blind, nonrandomized study suggested double-blind, placebo-controlled trial, included 519 patients
that the benefits of high-dose MRA therapy in AHF included with AHF with evidence of volume overload to receive pre-
lower natriuretic peptide levels, less clinical congestion, bet- emptive or early acetazolamide (500 mg intravenously for
ter renal function, and less need for an intravenous diuretic 3 days) or placebo added to treatment with loop diuretics
[15]. However, the first large clinical trial on pre-emptive [18••]. All patients were receiving oral maintenance diuretic
combined diuretic treatment (ATHENA-HF trial: Efficacy therapy with at least 40 mg of furosemide (or an equivalent
and Safety of Spironolactone in Acute Heart Failure) that dose of other loop diuretics). Concomitant treatment with
randomized 360 patients with AHF treated with loop diu- sodium-glucose cotransporter-2 inhibitors (SGLT2i) and
retics to receive high doses of spironolactone (100 mg per an estimated glomerular filtration rate (eGFR) < 20 mL/
day) or placebo for 96 h did not improve the primary end- min/1.73m2 were exclusion criteria. The trial intervention
point (change in N-terminal pro-B-type natriuretic peptide led to significantly greater rates of successful decongestion
levels) or any of the secondary efficacy endpoints (clinical 3 days after randomization. In addition, the acetazolamide
congestion score, dyspnoea assessment, net urine output, group achieved more natriuresis, shorter hospital stays, and
and net weight change) [16]. Despite the limitations of the more chances of getting discharged without residual con-
ATHENA-HF trial, given its neutral results and the concerns gestion. The effect of acetazolamide on the primary end-
regarding safety (hyperkalaemia and kidney dysfunction), point was consistent across prespecified subgroups, except
the use of MRA at high doses is not recommended. for patients receiving a higher maintenance dose of loop
 Current Heart Failure Reports

diuretics, who had less benefit than those receiving a lower The CLOROTIC (Combining loop with thiazide diuret-
maintenance dose. Therefore, it is questionable whether ics for decompensated heart failure) trial was a pragmatic
acetazolamide will be useful as a diuretic resistance treat- clinical trial that answered some of these questions. In this
ment strategy. In terms of safety, the incidence of worsening multicentre, randomized, double-blind, placebo-controlled
renal function (WRF) (defined as the doubling of the serum trial, patients hospitalized due to AHF with at least 1-month
creatinine level from baseline, a decrease of at least 50% in prior treatment with an oral loop diuretic (furosemide dose
the eGFR, or receipt of renal-replacement therapy), hypoka- 80–240 mg or equivalent) were assigned to receive oral
laemia, hypotension, and adverse events were similar in the hydrochlorothiazide (HCTZ) or placebo for 5 days, in addi-
two groups [18••]. However, when WRF was defined as an tion to a standardized intravenous furosemide regimen. The
increase in creatinine of at least 0.3 mg/dL, acetazolamide use of high doses of furosemide at baseline is a surrogate
was associated with a higher incidence of this event (40.5% indicator that many patients included in the CLOROTIC
vs. 18.9%) [19]. The prespecified subanalysis of the trial trial were resistant to loop diuretics. Oral HCTZ doses
showed that the intervention was successful at achieving were adjusted according to three eGFR categories as fol-
decongestion across the entire range of renal function (with lows: > 50 mL/min/1.73 ­m2, 25 mg once daily; 20–50 mL/
more pronounced beneficial effects in patients with lower min/1.73 ­m2, 50 mg once daily; and < 20 mL/min/1.73 m ­ 2,
eGFR), and baseline left-ventricle ejection fraction (LVEF) 100 mg once daily [25••]. The main finding was that HCTZ
[19, 20]. Furthermore, acetazolamide was effective over the resulted in greater weight loss at 72 h compared with pla-
entire range of baseline serum bicarbonate, but some signals cebo. The coprimary endpoint of patient-reported dyspnoea
indicated that patients with more elevated bicarbonate exhib- within the same time frame showed no significant differ-
ited a more pronounced response to acetazolamide, and this ences between diuretic strategies. The effect of HCTZ on
fact could indicate that this form of diuretic resistance could the primary endpoint was consistent across different sub-
be targeted by acetazolamide [21]. groups. Safety outcomes were also assessed, including the
It is essential to mention that patients on SGLT2i (drugs proportion of patients whose serum creatinine increased by
with a mechanism of action also in the proximal tubule) 0.3 mg/dL (> 26.5 µmol/L), which occurred more commonly
were excluded, and then the generalizability of the results in patients receiving HCTZ vs. placebo (46% vs. 17%). Rates
of the ADVOR trial among patients on SGLT2i remains of severe hypokalaemia or hyponatraemia were also similar
unclear and will require further studies. between diuretic strategies, as were the secondary endpoints
It is also important to consider that some measures taken of survival, HF rehospitalizations, and other serious adverse
by the investigators to mitigate adverse events, such as events. However, in a post hoc analysis using higher potas-
daily magnesium infusions and administering intravenous sium cut-off points (≤ 3.5 and ≤ 3.0 mmol/L), hypokalaemia
sodium bicarbonate or potassium when serum bicarbonate was more frequent in those who received HCTZ [25••].
was below 20 mEq/L or when serum potassium was below Similarly to the ADVOR trial, post hoc subanalysis
4 mEq/L, respectively, are not easy to replicate in clinical showed that the addition of eGFR-adjusted doses of oral
practice and should be considered necessary co-interven- HCTZ to loop diuretics in patients with AHF improved
tions when adding acetazolamide. diuretic response across the eGFR spectrum, but this effect
tended to be larger at higher eGFR [26]. Two additional post
hoc subanalyses have shown that the trial intervention was
Combining Thiazide with Loop Diuretics consistent across the entire range of LVEF [27] and without
differences according to sex [28].
Thiazides inhibit the sodium-chloride cotransporter in
distal convoluted tubules [22]. The evidence supporting
a thiazide and loop diuretic combination in AHF has been Combining Sodium‑Glucose Cotransporter‑2
limited to observational studies and a single 40-patient Inhibitors with Loop Diuretics
randomized study conducted before the current era of HF
foundational therapy [23, 24]. All these previous stud- Two small clinical trials (EMPA-REPONSE-AHF and
ies suggest that combination diuretic therapy using any of EMPAG-HF) analyzed for the first time the effect on
several thiazide-type diuretics can significantly increase decongestion of the pre-emptive initiation of a SGLT2i
urine sodium excretion and induce weight loss and oedema in patients with AHF. In both trials, the early addition of
resolution. However, there has always been concern about empagliflozin (10 mg and 25 mg in the EMPA-REPONSE-
the potential adverse events of this diuretic strategy, such AHF and EMPAG-HF trials, respectively) to standard diu-
as severe hypokalaemia, hyponatremia, hypotension, and retic therapy increased the urine output without affecting
worsening renal function [23]. renal function. However, there were no differences in the
Current Heart Failure Reports

dyspnoea scores and changes in body weight in comparison be treated with an SGLT2i at baseline, we believe the main
to placebo [29, 30]. question is not whether these will be superior to diuretics in
The EMPULSE trial (empagliflozin in patients hospital- achieving decongestion but whether the sequential nephron
ized for acute heart failure) showed that the pre-emptive or blockade combining different classes of diuretics (loop diu-
early initiation of empagliflozin vs. placebo in 530 patients retics plus thiazide diuretics and/or acetazolamide) on top of
hospitalized for AHF resulted in a significant clinical benefit SGLT2i will be safe and provide incremental decongestion
in the 90 days after starting treatment [31]. A prespecified efficacy. Treatment with SGLT2i was not recommended for
substudy of this trial evaluated the effect of empagliflozin HF during the enrolment period of the CLOROTIC trial and
on decongestion-related endpoints (weight loss, weight loss was an exclusion criterion for the ADVOR trial. Data from
adjusted for diuretic dose, change from baseline in NT- the abovementioned trials support the early initiation of an
proBNP, haemoconcentation and clinical congestion score). SGLT2i in AHF to facilitate decongestion while rapidly and
The initiation of empagliflozin in patients hospitalized for safely optimizing GDMT. Considering the benefits reported
AHF resulted in an improvement in all the decongestion with SGLT2i in patients with HF in the acute setting [31,
endpoints. This reduction was observed at all evaluated time 34], the demand for safe and efficacious combination diu-
points (15, 30, and 90 days) and, additionally, patients with retic regimens may need re-evaluation in AHF cohorts with
greater weight loss (above the median) were more likely to concomitant SGLT2i use.
experience a net clinical benefit at 90 days [32••].
The DICTATE-AHF trial examined the efficacy and
safety of dapagliflozin initiated within 24 h of hospital pres- Other Diuretic Combination Strategies
entation on diuretic response in patients with AHF. Although
the primary outcome did not achieve significance, the results Tolvaptan, a competitive vasopressin V2-receptor antago-
of this trial show a trend toward increased diuretic efficiency nist, is an oral diuretic that acts on the distal portion of the
with the addition of dapagliflozin compared with placebo nephron, promoting free water excretion. Evidence from
among patients admitted with AHF and requiring intrave- clinical trials showed that tolvaptan, in combination with
nous loop diuretics [33]. loop diuretics, is well tolerated in patients with conges-
A small multicentre, open label, randomized clinical trial tive HF [35]. It also ameliorates symptoms of congestion,
(DAPARESIST trial) compared the addition of dapagliflozin increases sodium concentration in patients with hypona-
or metolazone to loop diuretic treatment in patients hos- tremia, reduces loop diuretic dose, and lowers the risk of
pitalized with HF who remained congested despite treat- hypokalaemia. However, these findings are inconsistent
ment with intravenous furosemide, this being a surrogate among studies, and moreover, these studies were not focused
marker of diuretic resistance [34]. The study suggests that on patients with diuretic resistance [35, 36]. A possible sce-
both dapagliflozin and metolazone were similarly effective nario in which the usefulness of tolvaptan has been sug-
at relieving congestion when added to intravenous furo- gested is in patients with refractory HF and hyponatremia
semide in patients with diuretic resistance. However, in [37]. Based on these considerations, the DR-AHF (Tolvap-
our opinion, some of the results discussed in the DAPA- tan add-on Therapy to Overcome Loop Diuretic Resistance
RESIST trial might be an overinterpretation and should be in Acute Heart Failure With Renal Dysfunction) trial is an
commented on in depth. First, in the DAPARESIST trial, ongoing study designed to demonstrate the effectiveness of
the dose of metolazone was chosen at physicians’ discre- early tolvaptan as add-on therapy in AHF patients with renal
tion (5 or 10 mg) based on their clinical experience and dysfunction and diuretic resistance [38].
was not adjusted for renal function, resulting in a rather On the other hand, several studies (mostly conducted
low median daily dose of 5.4 mg daily. Second, treatment in European countries) have shown that administration of
groups at baseline were not balanced in terms of congestion. intravenous hypertonic saline (HS) given concomitantly
Patients assigned to receive metolazone had more signs of with high doses of loop diuretics can improve diuresis, renal
congestion: more elevated jugular venous pressure, pulmo- function, and clinical outcomes in patients with AHF [39].
nary crepitations, ascites, and pleural effusion and higher However, the use of HS in AHF has been questioned by
scores in a modified ADVOR clinical congestion score than the scientific community for different reasons, including a
those assigned to dapagliflozin. Finally, the cumulative and retraction and subsequent exclusion from a meta-analysis
median doses of loop diuretics after randomization were based on concerns regarding data validity [40]. This retrac-
higher in patients who received dapagliflozin. As such, one tion, in conjunction with the counterintuitive nature of
might also conclude that patients assigned to dapagliflozin administering salt in an effort to remove salt, is one of the
had lower diuretic efficiency than those assigned to (low reasons why HS has never been included in the guidelines
dose) metolazone despite being less congested and receiving [5] and has led to a slow adoption of this treatment strategy
higher doses of furosemide. Now that most HF patients will in many countries, including the United States [41]. These
Table 1  Comparison of combination diuretic trials in acute heart failure
ATHENA-HF ADVOR CLOROTIC DAPA-RESIST DICTATE-AHF EMPULSE*
22 sites (USA) 27 sites (Belgium) 26 sites (Spain) 7 sites (UK) N = 240 118 sites (15 countries)
N = 360 N = 519 N = 230 N = 61 N = 530

Study design
Intervention High-dose spironolactone IV acetazolamide Oral hydrochlorothi- Dapagliflozin 10 mg vs. Dapagliflozin 10 mg vs. Empagliflozin 10 mg vs.
(100 mg) vs. placebo (500 mg) vs. placebo azide (eGFR > 50 mL/ Metolazone 5–10 mg placebo until day 5 or placebo for 90 days
(or 25 mg spironolac- for 3 days min: 25 mg; eGFR for 3 days hospital discharge
tone) for 4 days 20–50 mL/min: 50 mg;
eGFR < 20 mL/min:
100 mg) vs. placebo for
5 days
Primary endpoint Change in NT-proBNP Successful decongestion Changes in weight and Change in weight from Diuretic efficiency Hierarchical composite
levels from baseline 3 days after randomiza- patient-reported dysp- randomization to 96 h (weight loss per 40 mg of all-cause death, HF
to 96 h tion noea at 72 h of furosemide) at day 5 events, or a ≥ 5 point
change in the KCCQ-
TSS at 90 days
Secondary endpoints 1. Clinical congestion 1. Mortality or HF read- 1. Changes in weight 1. Change in congestion 1. Worsening AHF dur- 1. Weight loss
score mission at 90 days and patient-reported assessed using LUS ing index hospitaliza- 2. Loop diuretic efficiency
2. Changes in patient- 2. Hospital length of stay dyspnoea at 96 h 2. Loop diuretic effi- tion (weight loss per 40 mg of
reported dyspnoea 2. Metrics of diuretic ciency (weight loss per 2. Readmission for AHF furosemide)
3. Diuresis at 96 h ­responsea 40 mg of furosemide) or diabetes mellitus 3. Change in NT-proBNP
4. Change in weight at 3. Hospital length of stay 3. Modified ADVOR 3. 24-h diuresis levels over 30 days of
96 h 4. Mortality and/or read- congestion score 4. 24-h natriuresis treatment
5. Loop diuretic dose at mission at 30/90 days 4. Hemoconcentration
discharge 5. Clinical congestion
6. Development of in- score
hospital WHF
7. All-cause mortality
and all-cause readmis-
sion at 30 days
Safety endpoints WRF: increase in serum WRF: increase in WRF: increase in serum WRF: increase in serum 1. Diabetic ketoacidosis Acute renal failure (includ-
creatinine > 0.3 mg/dL serum creatinine × 2 creatinine > 0.3 mg/ creatinine > 0.3 mg/dL 2. Hypotension ing acute kidney injury,
Hyperkalaemia (moder- or decrease in dL or decrease in Hypokalaemia 3. Hypoglycaemia subacute kidney injury,
ate > 5.5 mmol/L and eGFR > 50% eGFR > 50% (K +  < 3.5 mmol/L) 4. Genitourinary infec- anuria, oliguria, azotae-
severe > 6.0 mmol/L) Hypokalaemia Hypokalaemia Hiponatremia tions mia, renal failure, renal
(K +  < 3.0 mmol/L) (K +  < 2.5 mmol/L)b (Na +  < 125 mmol/L) 5. Median change in impairment, and renal
Hypotension Hiponatremia Hyperkalaemia eGFR replacement therapy)
(SBP < 85 mmHg) (Na +  < 125 mmol/L)b (K +  > 5.5 mmol/L)
Hypotension
(SBP < 90 mmHg)
Baseline characteristics
Age (years) 65 78 83 79 65 71
Female sex 36% 37% 48% 54% 39% 34%
Hypertension 84% 75% 89% N.A N.A 80%
Current Heart Failure Reports
Table 1  (continued)
ATHENA-HF ADVOR CLOROTIC DAPA-RESIST DICTATE-AHF EMPULSE*
22 sites (USA) 27 sites (Belgium) 26 sites (Spain) 7 sites (UK) N = 240 118 sites (15 countries)
N = 360 N = 519 N = 230 N = 61 N = 530
Diabetes mellitus 41% 47% 57% 46% 71% 45%
Atrial fibrillation 48% 72% 69% 67% N.A 49%
Ischemic aetiology 63% 45% 33% 33% N.A 25%
Current Heart Failure Reports

LVEF (%) 34% 43% 55% 45% N.A 31%

Preserved LVEF (%) 27% (LVEF > 45%) 57% (LVEF > 40%) 75% (LVEF > 40%) 56% (LVEF > 40%) 48% (LVEF > 40%) 32% (LVEF > 40%)
Creatinine (mg/dL) 1.2 1.5 1.4 1.5 N.A N.A
eGFR (mL/ 56 39 43 41 53 52
min/1.73m2)c
NT-proBNP (pg/mL) 4102 6173 4525 4053 3202
Baseline treatment
ACEi/ARB/ARNI 60% 52% 55% 31% N.A 70%
Beta-blocker 74% 81% 60% 74% N.A 79%
MRA 11% 42% 35% 36% N.A 52%
Loop diuretics 96% 100% 100% 89% N.A 82%
Dose of oral furosem- 80 60 80 N.A N.A N.A
ide (mg/day)
Main findings Adding high-dose The addition of aceta- Adding oral hydro- Dapagliflozin was not Early dapagliflozin initia- Initiation of empagliflozin
spironolactone in AHF zolamide to loop diu- chlorothiazide to IV more effective at reliev- tion did not result in a in patients hospitalized
did not improve the retic therapy in patients furosemide improved ing congestion than statistically significant for AHF resulted in
primary or secondary with AHF resulted in the diuretic response metolazone. Patients improvement in diuretic an early, effective and
efficacy end points. a greater incidence of in patients with AHF assigned to dapagliflo- efficiency but did not sustained decongestion
There were no safety successful decongestion but was associated with zin received a larger worsen any prespeci- which was associated
concerns as high-dose with no safety concerns higher rates of WRF cumulative dose of fied safety outcomes with clinical benefit at
spironolactone was safe and hypokalaemia furosemide but experi- day 90
and well tolerated enced less biochemical
upset
ACEi angiotensin-converting enzyme inhibitor, ARB angiotensin-receptor blocker, ARNI angiotensin receptor neprilysin inhibitor, eGFR estimated glomerular filtration rate, HF heart failure,
IV intravenous, KCCQ-TSS Kansas City Cardiomyopathy Questionnaire Total Symptom Score, LUS lung ultrasound, LVEF left-ventricular ejection fraction, MRA mineralocorticoid receptor
antagonist, N.A. not available, NT-proBNP N-terminal pro-B-type natriuretic peptide, SBP systolic blood pressure, WHF worsening heart failure, WRF worsening renal function
*
Pre-specified subanalysis of decongestion-related endpoints of the EMPULSE study
a
The metrics of diuretic response included a 24-h diuresis quantification, weight loss per 40 mg of furosemide (at 72 and at 96 h), net fluid loss (24-h diuresis) per milligramme of furosemide
and mean loop diuretic dose administered from time of study enrollment to 72 h
b
A post hoc analysis using higher K + (≤ 3.5 and ≤ 3.0 mmol/L) and Na + (< 130 mmol/L) cut-off points was also conducted
c
An eGFR < 20 mL/min/1.73 ­m2 was an exclusion criteria for the ADVOR, DAPA-RESIST, and EMPULSE trials; an eGFR < 25 mL/min/1.73 m ­ 2 was an exclusion criteria for the DICTATE-
2
AHF trial; an eGFR < 30 mL/min/1.73 m
­ was an exclusion criteria for the ATHENA-HF trial; in the CLOROTIC trial baseline, eGFR values were not an exclusion criterion, except if patients
required renal replacement therapy
 Current Heart Failure Reports

Fig. 2  The diuretic pyramid

findings and arguments suggest that additional rigorous is an understudied but promising decongestive strategy in
clinical trials, including HS as a therapeutic agent for AHF, the AHF cohort with diuretic resistance but prospective and
are warranted [42]. controlled studies are required.

Multinephron Segment Diuretic Therapy Combinational Diuretics in the Ambulatory

Setting
Multinephron segment diuretic therapy (MSDT), defined as
the simultaneous use of 3–4 diuretic classes with actions The few clinical trials on combined diuretic regimens
along the proximal tubule, the loop of Henle, the distal have been carried out in hospital-admitted patients dur-
tubule, and the collecting duct, is a potential method to over- ing the acute decompensation phase, with even less evi-
come severe diuretic resistance in AHF. MSDT uses diuret- dence during the post-discharge stable phase in the out-
ics with action in multiple nephron segments to counter the patient setting. Recently, the TRANSFORM-HF trial
nephron’s adaptations. MSDT has been recommended for (the largest clinical trial of diuretics in outpatient HF
severe diuretic resistance with only expert opinion and case- patients) compared torsemide with furosemide in 2859
level evidence, and its major barrier is the absence of safety patients discharged after hospitalization for HF and did
data [43, 44]. A more recent retrospective study conducted not find significant differences in all-cause mortality over
in a United States centre included 167 patients hospitalized 12 months. It would be interesting to know the effect of
for AHF with diuretic resistance treated with simultaneous the concomitant use of thiazide diuretics with either tor-
diuretics comprising an oral carbonic anhydrase inhibitor, semide or furosemide in this clinical trial, although this
intravenous loop diuretic, oral or intravenous thiazide, and analysis was not reported [46]. A recent large multicentre
oral MRA. MSDT was associated with a significant diuretic observational cohort study conducted in Spain, including
response in approximately two-thirds of the total cohort and more than 14,000 patients discharged after an AHF hos-
one-half of patients with severe diuretic resistance without pitalization, found that 9.5% of patients were discharged
substantial changes in serum electrolytes, extreme electro- with the combination of thiazide and loop diuretics, while
lyte repletion, or worsening kidney function [45]. MSDT the rest (90.5%) were discharged with only loop diuretics
Current Heart Failure Reports

on top of the rest of standard-of-care treatments. Com- Conclusion

bining thiazide and loop diuretics after discharge showed
a neutral effect on all the analyzed outcomes (all-cause Until recently, the evidence on combined diuretic treatment
mortality and hospitalization) [47]. The DEA-HF (Heart in AHF was based on observational studies and expert expe-
Failure Diuresis Efficacy Comparison) study is an ongo- rience. The recent evidence from clinical trials has shown
ing randomized, open-label, cross-over study comparing that combined diuretic treatment can be started earlier with-
three diuretic regimens in patients with HF in the ambula- out escalating the doses of loop diuretics with a good safety
tory setting (furosemide, furosemide plus metolazone, and profile. However, more studies on the pathophysiology of
furosemide plus acetazolamide) perhaps will provide some diuretic resistance and larger clinical trials combining dif-
evidence in this context [48]. ferent diuretics would be necessary to personalize treatment
by adapting it to nephron remodelling.

Practical Recommendations: the Diuretic Author Contributions JCT wrote the main manuscript text. JCT and
JLM prepared the figures. All authors reviewed the manuscript and
Pyramid in the Treatment of Congestion approved the final version.
in Acute Heart Failure
Funding No funding was received.
After reviewing the evidence from the latest clinical trials
Data Availability No datasets were generated or analyzed during the
(summarized in Table 1) and based on our expertise, we current study.
propose a practical and personal approach to the combina-
tion of diuretics in patients with AHF (Fig. 2). Unless con- Declarations
traindicated, the vast majority of patients with AHF should
be treated with a SGLT2i. The first therapeutic step should Competing Interests JC received consulting and lecture fees from
AstraZeneca, Boehringer Ingelheim, Novartis and Vifor Pharma (out-
be loop diuretics, which should be prescribed depending on side the submitted work). MCM reports personal fees or advisory
whether the patient is “de novo” or chronic decompensated boards from AstraZeneca, Boehringer Ingelheim, Bayer, Novartis,
HF and according to previous exposure to loop diuretics and NovoNordisk, Rovi, and Vifor Pharma (outside the submitted work).
congestion severity [5, 49]. In our opinion, the combina- JLMR received consulting and lecture fees from AstraZeneca,
Boehringer Ingelheim, Esteve and Zambon. JN reports personal fees
tion of diuretics is more justified in patients with chronic or advisory boards from Alleviant, AstraZeneca, Boehringer Ingelheim,
decompensated HF with prior exposure to high doses of loop Bayer, Novartis, NovoNordisk, Pfizer, Rovi, and Vifor Pharma (outside
diuretics and unequivocal data of congestion [22, 50]. We the submitted work). LM reports personal fees or advisory boards from
recommend an early addition of a second diuretic agent if AstraZeneca, Boehringer Ingelheim, Lilly, Bayer, Novartis and Rovi
(outside the submitted work). JCT and FF declare that they have no
diuretic resistance appears after loop diuretic optimization. conflict of interest.
The choice between HCTZ and acetazolamide can be con-
troversial since there is no head-to-head comparison. HCTZ Human and Animal Rights and Informed Consent This article does not
might be preferential in patients with diuretic resistance contain any studies with human or animal subjects performed by any
of the authors.
receiving chronic high doses of loop diuretics and acetazola-
mide in the case of metabolic alkalosis and/or lower chronic
loop diuretic doses. In both cases, if baseline potassium is
below 4 mEq/L, it is recommended to administer potassium
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2017;4:130–7. https://​doi.​org/​10.​1002/​ehf2.​12124. Springer Nature or its licensor (e.g. a society or other partner) holds
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on therapy to overcome loop diuretic resistance in acute heart author(s) or other rightsholder(s); author self-archiving of the accepted
failure with renal dysfunction (DR-AHF): design and rationale. manuscript version of this article is solely governed by the terms of
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