Cardiomyopathy and Heart Failure

Diuretic Therapy in Heart Failure – Current Approaches

Ga v ino Ca s u a n d Pi e r l u i g i M e r e l l a

San Francesco Nuoro Hospital, Nuoro, Italy

Abstract
The use of diuretics is common in patients with heart failure (HF), to relieve the congestive symptoms of HF. Although they are widely
used, there are limited data on their ability to modulate HF-related morbidity and mortality. Diuretic efficacy may be limited by adverse
neurohormonal activation and by ‘congestion-like’ symptoms. Diuretics are an extremely useful and varied class of agent for the management
of hypervolaemic states. This review summarises the basic features of diuretics, including their mechanism of action, indications and adverse
effects in heart failure.

Keywords
Heart failure, diuretic therapy, diuretic resistance, loop diuretics, thiazide diuretics, potassium-sparing diuretics

Disclosure: The authors have no conflicts of interest to declare.

Acknowledgement: The authors want to thank Dr Paola Berne for helpful discussions during the writing of this paper.
Received: 5 May 2015 Accepted: 5 July 2015 Citation: European Cardiology Review, 2015;10(1):42–7
Correspondence: Gavino Casu, Cardiology Department, San Francesco Nuoro Hospital, Via Mannironi 1, 08100 Nuoro, Italy. E: [email protected]

Heart failure (HF) is a syndrome defined by the failure of the heart to effects, such as reduction in pulmonary wedge pressure.6 However, it is
deliver oxygen at a rate commensurate with the requirements of the important to recognise that the diuretic actions of loop diuretics may be
metabolising tissues, despite normal filling pressures (or only at the decreased by the concomitant use of non-steroidal anti-inflammatory
expense of increased filling pressures),1 secondary to an abnormality of drugs (NSAIDs), possibly because this inhibits renal prostaglandin
the cardiac structure or function. synthesis. Loop diuretics include furosemide, bumetanide, torsemide
and ethacrynic acid.
HF is the most common cause of hospitalisation in patients over the age
of 65.2 The main manifestations of the syndrome are symptoms resulting While the bioavailability of oral furosemide ranges from 40 to 80  %, the
from vascular congestion, such as shortness of breath, abdominal bioavailability of torasemide and bumetanide exceeds 80 %; so these two
distension, oedema formation and symptoms resulting from low systemic molecules may be more effective in treating patients suffering from HF.7
perfusion. HF syndrome is of relevant economic importance and in the
ADHERE study signs and symptoms of congestion were the most frequent A well-known consequence of loop diuretic therapy is depletion of other
cause of hospital admission.1 Congestion often develops gradually before electrolytes, such as potassium, magnesium, calcium and chloride (see
admission and many patients may have elevated left ventricular (LV) filling Table 1).
pressures even when congestion (dyspnoea, jugular venous distension
or oedema)3 is absent. Diuretic therapy, and especially loop diuretic Thiazide Diuretics and Metolazone
therapy, are the usual way of managing congestion, especially in volume- Benzothiazide diuretics inhibit the sodium–chloride transporter at
overloaded patients.4 The most commonly used diuretics in HF are loop the distal portion of the ascending limb and the first part of the distal
diuretics, thiazides and potassium-sparing diuretics. tubule. They prevent maximal dilution of urine, thus increasing free
water clearance and excretion of sodium and chloride through the renal
This review focuses on the classes of diuretics, their role in cases of tubular epithelium. The increased delivery of sodium to the collecting
HF with volume overload and current approaches when treating this ducts enhances the exchange of sodium with potassium and, as a
complex subset of patients. result, potassium depletion.

Class of Diuretics They are less effective in patients with reduced glomerular filtration,
Loop Diuretics because they exert their diuretic effects from the luminal side of the
Loop diuretics, reversibly, inhibit the Na+⁄2Cl-⁄K+ co-transporter of the nephron. Although they are less potent than loop diuretics, they may
thick ascending loop of Henle where one-third of filtered sodium is work in synergy with them when a sequential segmental nephron
reabsorbed. This causes decreased sodium and chloride reabsorption blockade is achieved.
and increased diuresis.5
Thiazides also decrease peripheral vascular resistance by a mechanism
Loop diuretics also enhance the synthesis of prostaglandins, which which is, at present, not well understood, resulting in a decrease of
cause renal and venous dilatation. This explains some of the cardiac blood pressure.8

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 Diuretic Therapy in Heart Failure – Current Approaches

Table 1: Summary of Diuretic Drugs used in Heart Failure

Drug Site of Action Duration Common Starting Dosage Maximum Common Side Effects
of Action Dosage
Loop diuretics Inhibition of Na-K-CI Hypokalaemia, hypomagnesaemia,
co-transporter in the thick hyperuricaemia, hypocalcaemia,
ascending loop of Henle hyponatraemia, otoxicity
Furosemide 7h 20 to 40 mg once or twice 600 mg
Bumetanide 4 to 6 h 0.5 to 1.0 mg once or twice 10 mg
Torasemide 12 to 16 h 10 to 20 mg once 200 mg
Ethacrynic acid 6h 25–50 mg once or twice 200 mg
Thiazide-like Inhibition of Na-Cl Hypokalaemia, hypomagnesaemia,
diuretics transporter at distal hypercalcaemia, hyponatraemia,
nephron hyperuricaemia
Chlorothiazide 6 to 12 h 250 to 500 mg Once or twice 1,000 mg
Chlorthalidone 24 to 72 h 12.5 to 25 mg once 100 mg
Indapamide 36 h 2.5 mg once 20 mg
Potassium-sparing Inhibition of mineralcarticoid Hyperkalaemia
diuretics receptor or its effectors at
distal nephron
Amiloride 24 h 5 mg once 20 mg
Triamterene 7 to 9 h 50 to 75 mg twice 200 mg
Spironolactone 1 to 3 h 12.5 to 25.0 mg once 50 mg Gynecomastia

Metolazone is not a thiazide but acts in a similar way. Metolazone is however, less effective in patients with reduced kidney function.10 As
more potent than hydrochlorothiazide and retains its effectiveness a general rule, doses of loop diuretics should be as low as possible, in
even when there is severe glomerular filtration rate (GFR) reduction. order to maintain a euvolaemic state. Restricting the amount of sodium
and water, daily weight monitoring and avoidance of NSAIDs are critical
Potassium-sparing Diuretics in preventing salt and water retention.
The potassium-sparing diuretics used for treating HF are the
aldosterone receptor antagonists spironolactone and eplerenone. The commonly used loop diuretics only act for a short time, so
They act at the cortical collecting duct, in particular by reducing the common therapy schemes require twice-daily administration, in order
absorption of sodium and water and increasing the excretion of to avoid post-diuretic rebound sodium retention.
hydrogen ions and potassium, and their action is mediated by the
antagonism of the actions of mineral corticoids. Only 3  % of filtered Furosemide is by far the most common oral loop diuretic, but
sodium is reabsorbed at the collecting duct, so this class of drugs does patients with resistance to oral furosemide therapy may benefit from
not have an appreciable diuretic effect. However they are often used trials with second-generation oral loop diuretics (bumetanide and
in association with other more effective diuretics to correct or prevent torasemide). These may be more efficacious, due to their increased
potassium deficiency. They are also significantly efficacious in reducing oral bioavailability and potency. The longer half-life of torasemide
the deleterious effects of aldosterone on the cardiovascular system. may limit the previously described rebound phenomenon.11 In the
Spironolactone is a non-selective aldosterone receptor antagonist, prospective TORasemide In Chronic heart failure (TORIC) study, the use
and thus endocrine-related adverse effects (such as gynecomastia) are of torasemide was associated with lower mortality than furosemide
relatively common when it is used. Eplerone has greater selectivity on in patients with HF. Furthermore, torasemide has been reported to
the mineral corticoid receptor, and has fewer side effects.9 attenuate LV remodelling in patients with congestive HF (CHF) to a
greater extent than furosemide.12 Torasemide has also been reported
Diuretics in Chronic Heart Failure to attenuate LV remodelling in patients with HF to a greater extent than
Diuretics are used to achieve and maintain euvolaemia (the patient’s furosemide.13 Although international guidelines do not define which
‘dry weight’) with the lowest possible dose. This means that the dose diuretic should be preferred, there is not enough strong evidence to
must be adjusted, particularly after restoration of the dry body weight, recommend torasemide and bumetanide over furosemide in HF.
to avoid the risk of dehydration, which leads to hypotension and renal
dysfunction.10 It is important that treatment with diuretics is always Careful monitoring and supplementation of electrolytes, particularly
coupled with neuro-hormonal system blocking, in order to slow down potassium and magnesium, are a crucial aspect of loop diuretic therapy.
the progress of the disease.
Randomised clinical trials have shown that potassium-sparing diuretics
In general, due to their greater effectiveness, loop diuretics, such as are able to reduce both hospitalisations and mortality in patients
furosemide, are the mainstay of diuretic therapy in HF. Indeed loop with chronic HF, although they are less useful than loop diuretics
diuretics produce more intense and shorter diuresis than thiazides, in cases of acute decompensate HF.14 Aldosterone levels are elevated in
which results in more gentle and prolonged diuresis. They are, patients with acute decompensated heart failure (ADHF) despite the

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Cardiomyopathy and Heart Failure

Figure 1: Schematic of a Dose‐response Curve of Loop prevalence of diuretic resistance in the HF population is unknown due to
Diuretics in Heart Failure Patients Compared with Controls the heterogeneity of the populations studied, the frequent comorbidity,
the different treatment regimens, as well as to the different definitions
used in various clinical trials. In a retrospective analysis of 1,153 patients
Normal
with advanced HF, 402 patients had diuretic resistance (defined in this
Fractional exceretion of sodium

Diminished study as requirement of furosemide >80  mg or bumetanide >2  mg

maximal
daily).20 Diuretic resistance was independently associated with total
responsiveness
Heart failure mortality, sudden death and pump failure death. Loop diuretics are
‘threshold drugs’. HF shifts the dose-response curve for loop diuretics
downward and to the right. Thus a higher starting dose of loop diuretics
Higher doses
is needed in order to achieve the same level of sodium excretion.21
required to
achieve same
diuretic effect The shift of the dose–response curve in HF implicates insufficient dosing
as a common cause of a lack of diuretic response (see Figure  1).21,22
The magnitude of natriuresis following a defined dose of diuretics
Diuretic concentration declines over time, even in normal subjects. This is the so-called ‘braking
In heart failure patients, higher doses are required to achieve a given diuretic effect and phenomenon’ and it is the result of both haemodynamic changes at
the maximal effect is blunted. Adapted, with permission, from Ellison21 and reprinted, with
permission, from Felker Reproduced with permission from Felker.22 the glomerulus as well as adaptive changes in the distal nephron. In a
seminal study on rats by Kaissling, furosemide treatment was associated
use of angiotensin-converting enzyme inhibitors, angiotensin receptor with cell hypertrophy at the distal convoluted tubule, the connecting
blockers and beta-blockers. In this setting, aldosterone elevation may tubule and the cortical collecting duct.23 These structural changes
contribute to cardiorenal dysfunction, increasing the risk of death and after furosemide treatment suggest an increase in active transcellular
ventricular arrhythmias.15,16 transport capacity of this segment.24 A partial explanation of these
anatomical modifications may be the increased stimulation mediated
Studies have shown benefits using aldosterone antagonists in HF by the renin-angiotensin and sympathetic nervous systems.23 An abrupt
using non-diuretic doses of mineralcorticoid receptor antagonists. The increase in diuretic resistance in HF patients may be due to concomitant
objective was to completely inhibit the angiotensin–aldosteron axis. In NSAID use or to an excessive intake of sodium. This may result in renal
the Emphasis-HF study, a double-blinded trial enrolling patients with function deteriorating and development of cardiorenal syndrome.25
chronic HF and low ejection fraction (EF), the aldosterone antagonist
eplerenone compared with placebo showed a significant reduction A response reduction to diuretic therapy is a common problem in patients
in deaths from all causes, hospitalisation for HF and of the primary with HF and while many studies have tried to give an exact clinical
outcome (cardiovascular death or hospitalisation for HF).17 definition of diuretic resistance, others have tried to find a solution to
the clinical problems that this causes. Probably the single most used and
For these reasons, their use is strongly recommended in patients with reproducible marker of cardiovascular congestion is body weight. As a
HF. Their greater usefulness, as has already been mentioned, is not their result, HF guidelines advocate daily body weight monitoring in order to
diuretic properties, but their ability to antagonise the many harmful effects detect the pre-symptomatic phase in patients at risk to develop acute
of hyperaldosteronism on the cardiovascular system. There are few decompensated HF.10 An interesting attempt to create a quantitative
studies in the literature describing the usefulness of high diuretic doses index of response to diuretic therapy was undertaken by Valente el al.26
of aldosterone antagonists in ADHF in order to overcome congestion. This index was obtained by comparing the administered dose of diuretic
In a exploratory study in ADHF patients, high doses of mineralcorticoid with the reduction of body weight and was intended to measure its
receptor antagonists (in more detail, about 100 mg spironolactone) were effectiveness. It showed a significant correlation with relevant clinical
safe and were also associated with an earlier resolution of the congestive variables and also highlighted a correlation with adverse events.
signs and with a more pronounced N-terminal of the prohormone brain
natriuretic peptide (NT-proBNP) reduction.18 In another study, Testani et al. tested a metrical index of diuretic
efficiency, which was defined as the net fluid lost per milligram of
Potassium-sparing diuretics have the disadvantage that their use loop diuretic, thus demonstrating that low diuretic efficiency during
results in a greater incidence of hyperkalaemia. However, when decongestive therapy portends poorer long-term outcomes in patients
combined with loop diuretics, as happens frequently in clinical practice, hospitalised with decompensated HF.27
this side effect is greatly reduced.
Once correctable variables and blockage of the neuroendocrine system
After overcoming the acute phase of HF, in selected subgroups it will have been excluded, a possible way of overcoming diuretic resistance
be possible to make an attempt to withdraw diuretics. A history of is to use infusion therapy to avoid the limitations of oral bioavailability.
hypertension, baseline furosemide dose of >40 mg/day, and a low LVEF For patients refractory to escalating doses of intravenous diuretics,
(<27 %) were independent predictors of diuretic restarting.19 options include use of continuous infusion rather than intermittent
boluses. This strategy was tested in the DOSE study,28 but no significant
Diuretic Resistance difference was noted between the two treatment groups.
Diuretic resistance is a common problem in HF patients. Removal of
excessive fluid is usually achieved by a combination of salt restriction Another approach is to administer two classes of diuretics together,
and loop diuretics, but in some cases congestion persists despite a loop diuretic combined with a thiazide-like diuretic, thus performing a
adequate diuretic therapy. This has been termed diuretic resistance. The sequential nephron blockade.29 Various mechanisms explain the success of

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 Diuretic Therapy in Heart Failure – Current Approaches

Figure 2: Mechanism of Diuretic Resistance

Cardiac failure

Loop diuretic
administration

Inhibition of Negative sodium

macula densa balance

Renin-angiotensin-aldosterone system

Secondary ↓ Distal sodium

hyperaldosteronism delivery
Natriuretic dose of
mineralocorticold
antagonist
Hypertrophy of distal nephron Thiazide diuretic
Increased expression of NaCl transporter

Natriuretic dose of
Mineralocorticold
mineralocorticold
receptor antagonist
antagonist

Loop diuretic
resistance
Reproduced with permission from Schrier et al.30

this combination strategy: the longer half-life of thiazide diuretics helps to alterations in glomerular haemodynamics due to neurohormonal and
counteract the rebound post-diuretic effect (see Figure 2).30 Thiazide-type intrarenal feedback mechanisms or from overt volume depletion.
diuretics inhibit sodium reabsorption in the distal nephron and primarily To address these common concerns we need to await results of
benefit patients who have distal nephron hypertrophy and hyperfunction ongoing clinical trials (between these, the ‘Safety and efficacy of
due to chronic treatment with loop diuretics. Indeed, inhibiting NaCl the combination of loop with thiazide type diuretics in patients with
transport along the distal tubule counteracts the reabsorption due to decompensated HF’, will compare the strategy of sequential block
hyper-functioning cells in the distal tubule. In addition, they markedly through add-on hydrochlorothiazide versus therapy with loop diuretics
increase the fractional sodium excretion, which is needed to achieve a alone). As a result of the above considerations, nowadays it is not easy
neutral or negative sodium balance if the GFR is depressed.31 to apply sequential nephron blockage to outpatient settings.34

Numerous thiazide-like diuretics have been evaluated in combination Diuretic Therapy in Acute Decompensated
with loop diuretics with similar results overall and there is no clear Heart Failure
evidence that any single thiazide-like diuretic is superior to another, Fluid overload is a major pathophysiological mechanism underlying
suggesting a class effect. It has been suggested that metolazone is both acute decompensation episodes of HF and the progress of the
superior to other thiazide-like diuretics in patients with advanced syndrome. Loop diuretics remain a cornerstone in the pharmacological
kidney disease, but other thiazide-like diuretics also increased the treatment of ADHF and are administered in about 90  % of patients
response to loop diuretics, even in patients with advanced renal hospitalised for HF.1 These drugs are routinely used as initial therapy in
failure. More recently, a small, retrospective, single-centre cohort study ADHF due to their ability to greatly improve the symptoms. Conversely,
compared two of the most commonly used thiazide-like diuretics because of their lower natriuretic effect, thiazide diuretics are used
(oral metolazone and intravenous chlorothiazide) as add-on therapy infrequently and are limited to cases where there is diuretic resistance.
to loop diuretics and no statistically significant differences in efficacy The same is true for potassium-sparing diuretics, which are only used
or safety were found.32 In some European countries, metolazone in cases of refractory oedema or concomitant hypokalaemia.
and chlorothiazide are not available and the most commonly
used thiazide-like diuretics for ADHF are hydrochlorothiazide and One of the major concerns of clinicians is the effect of excessive
chlorthalidone. Chorthalidone’s half-life (48–72 hours) is longer than diuretic therapy on the intra-arterial volume and, consequently, on the
that of hydrochlorothiazide (6–12 hours), which might increase risk of possible deleterious effects on renal function. Several studies have,
adverse events in patients hospitalised for ADHF. Moreover, head-to- indeed, demonstrated that there is a correlation between doses of
head studies comparing these for treating hypertension described an diuretics and the worsening of the prognosis in patients with acute
increased risk of hyponatraemia with chorthalidone.33 decompensated HF.35 However, no definite causal relationship has been
established between diuretic therapy, its dosage, and cardiovascular
For these reasons, hydrochlorothiazide or metalazone could be the mortality. It is, indeed, virtually impossible to distinguish between
diuretic of choice for treating ADHF. The main problem when using the multiple confounding factors, because sicker patients present
sequential nephron blockage is the excessive depletion of water and often with greater congestion and therefore receive higher doses of
electrolytes. Chronic thiazide diuretics use is a predictor of worsening diuretics. The pathophysiological basis of many of these concerns is
renal function in chronic HF and this is of concern, given the adverse that these drugs, which cause intravascular volume depletion, could
prognosis associated with worsening renal function in these patients. increase the hyperactivation of the neuroendocrine system with
Impaired renal function with diuretic therapy can result from direct resulting detrimental consequences.36,37

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Cardiomyopathy and Heart Failure

Nowadays, despite many studies in ADHF on diuretic therapy, the only water and small to medium weight solutes across a semi-permeable
certainty is that such therapies can relieve the patient’s symptoms and membrane to reduce volume overload.
reduce vascular congestion. It remains unclear what the preferred loop
diuretic should be, what should be the appropriate combination, what The first interesting, but controversial, data comes from the Ultrafiltration
is the optimal dosage and what should be the clinical goal. Current Versus Intravenous Diuretics for Patients Hospitalized for Acute
guidelines from the American College of Cardiology and the American Decompensated HF (UNLOAD) trial. In this study treatment with UF
Heart Association suggest that ‘Diuretics should be administered at doses resulted in significantly fewer hospital readmissions due to HF during
sufficient to achieve optimal volume status and relieve congestion without a 90-day follow-up.44 Unfortunately, the study was harshly criticised
inducing an excessively rapid reduction in intravascular volume.’38 because of the low doses of diuretics used and the consequent
reduced clinical reproducibility. In the recent Cardiorenal Rescue Study
New Approaches in Acute Decompensated Heart Failure (CARRESS-HF), a study designed
Although in the majority of patients congestion symptoms are controlled to compare the effect of UF with that of stepped pharmacological
by loop diuretic therapy, in a minority of cases other adjunctive therapy on renal function and weight loss in patients with HF who have
therapies are needed. This is because of the progression of the disease worsening renal function and persistent congestion, UF patients in the
or the worsening of the renal function. UF group had a significantly greater increase in serum creatinine and
more adverse events, including bleeding and vascular complications, as
Other solutions have been tested in addition to the aforementioned well as progressive renal dysfunction. Moreover, there was no significant
combination therapy (sequential nephron blockade). Some trials difference in the outcome, including mortality and rehospitalisation, at
demonstrated the positive effects of incorporating hypertonic saline 60 days.45 However the latest American guidelines suggest that UF may
solution (HSS) with standard loop diuretic therapy.39 In a large study be considered for use after all diuretic strategies have failed.38 Further
of 1,771 patients, the SMAC-HF study, in-hospital HSS administration, studies will be needed to assess what should be the exact role of UF in
combined with moderate sodium restriction, reduces hospitalisation the management of patients with ADHF.
time and increased diuresis. However, a long-term follow-up found that
moderate salt restriction was associated with a better prognosis than Conclusions
a low sodium diet.40 The potential benefits of this therapy are the faster HF remains the most common cause of hospitalisation in patients over
recovery of intra-arterial volume. This reduces the neuro-endocrine the age of 65 and the main symptoms are vascular congestion. Fluid
stimulation and improves glomerular perfusion, thus counteracting the overload is a major pathophysiological mechanism underlying both
common mechanisms that underlie fluid overload in various clinical acute decompensation in HF and the progression of the syndrome.
scenarios.36 Regardless, this was an unblinded study and use of HSS Although there has been a lot of controversy on the possible negative
is not recommended in current guidelines. Larger prospective and effects of diuretic therapy, due to the reduced intra-arterial volume
blinded studies need to be undertaken before this approach can be with neuro-endocrine hyperactivation, no definite causal relationship
recommended for clinical use. has been established between diuretic therapy, its dosage and
cardiovascular mortality.
HF with concomitant severe hyponatraemia is of particular clinical
relevance, due to its particular prognostic and therapeutic implications.41 Although there are three main classes of diuretics (loop diuretics, thiazide
Such patients may benefit from treatment with arginin vasopressin diuretics with metolazone and potassium-sparing diuretics), loop diuretics
antagonist (vaptans). This class of drugs can be useful in several cases are most commonly used, because they have the most potent natriuretic
of resistance to diuretics because of their specific action mechanisms.42 action. Conversely, despite having a weak diuretic effect, potassium
Despite this and other anecdotal reports, after the results of the sparing diuretics have been shown to be significantly efficacious in
Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with improving the long-term prognosis in symptomatic HF patients.
Tolvaptan trial (Everest), tolvaptan is today approved by the US Food
and Drug Administration only for the treatment of clinically significant Nowadays, the primary role of thiazide-like diuretics in CHF is to attempt
hypervolaemic and euvolaemic hyponatraemia (serum sodium less to overcome diuretic resistance, thus performing a sequential nephron
than 125 meq/lL). This includes patients with HF and the syndrome of blockade when administered in association with loop diuretics.
inappropriate antidiuretic hormone secretion.
Despite various attempts, due to the many confounding factors and the
Indeed in the EVEREST trial, an international, multicentre, randomised, extreme heterogeneity of studied population, randomised trials failed
double-blind, placebo-controlled trial in a population of hospitalised to find any significant differences on optimal dosages and modality of
chronic HF patients, there was no difference in the global clinical administration of loop diuretics in acute HF.
status of the two groups, although the tolvaptan group had significantly
decreased dyspnoea on day 1, and decreased weight and oedema More data will be needed before using arginine vasopressin antagonist
after 7 days. It is noteworthy that patients in the tolvaptan group had clinically, since the results of randomised trials failed to show the
significantly decreased loop diuretic use compared with the placebo expected benefits. The same is true for UF – until stronger clinical data
group. Despite these initial results, the long-term primary outcome trial are available, its use will be limited to selected cases in accordance with
showed no significant difference in overall mortality.43 In the future It current guidelines.
would be interesting to design a specific clinical trial on use of vaptans
in patients who developed diuretic resistance. Research of new physiology-based approaches designed to offset the
primary determinants of water retention could improve the management
Another option to be used in most complex patients is the use of of patients affected by CHF. Until then, diuretic therapy will remain the
diuretics in association with ultrafiltration (UF) therapy. UF moves cornerstone in CHF. n

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 Diuretic Therapy in Heart Failure – Current Approaches

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