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Loop diuretics in heart failure

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Heart Fail Rev
DOI 10.1007/s10741-011-9245-3
Loop diuretics in heart failure
G. Michael Felker
Ó Springer Science+Business Media, LLC 2011
Abstract Congestion is a major component of the clinical
syndrome of heart failure, and diuretic therapy remains the
cornerstone of congestion management. Despite being
widely used, there is very limited evidence from prospective
randomized studies to guide the prescription and titration of
diuretics. A thorough understanding of the pharmacology of
loop diuretics is crucial to the optimal use of these agents.
Although multiple observational studies have suggested that
high doses of diuretics may be harmful, all such analyses are
confounded by the association of higher diuretic doses with
greater severity of illness and comorbidity. Recent data from
randomized trials suggest that higher doses of diuretics may
be more effective at relieving congestion and that associated
changes in renal function are typically transient. Data from
other ongoing trials will continue to inform our under-
standing of the optimal role for loop diuretics in the treat-
ment of heart failure.
Keywords Heart failure
Diuretics
Congestion

Clinical trials
Introduction
Heart failure is a major public health burden in the devel-
oped world and is associated with high morbidity, mortality,
and cost. Despite continued advances in therapy, the prog-
nosis of heart failure remains poor, with 5-year mortality
approaching 50% in symptomatic patients. Because many
G. M. Felker (&)
Divisions of Cardiology and Clinical Pharmacology, Duke
Clinical Research Institute, Duke University School of Medicine,
2400 Pratt St, Room 0311 Terrace Level, Durham,
NC 27705, USA
e-mail: michael.felker@duke.edu
of the primary clinical manifestations of heart failure are
due to fluid retention and congestion, congestion remains an
important target for heart failure therapies [1]. Diuretic
therapy remains the cornerstone of congestion management,
and loop diuretics are prescribed to the vast majority of
patients with symptomatic heart failure. Despite being
widely used, there is very limited evidence from prospec-
tive randomized studies to guide the prescription and
titration of diuretics. The traditional mainstay of evidence-
based medicine, the placebo-controlled, randomized clini-
cal trial, has not been robustly applied to diuretic therapy
until recently. Significant uncertainty persists about the best
way to utilize diuretics in patients with heart failure despite
the long history of this class of drugs. As an example, over
50% of unanswered questions in the day-to-day manage-
ment of heart failure patients at a tertiary care academic
medical center Ire related to the most appropriate use of
diuretics [2]. This is reflected in the level of evidence cited
by current clinical practice guidelines, all of which strongly
recommend the use of diuretic therapy to control volume
status although the level of evidence tends to be primarily
based on expert opinion [3–5]. Over the last decade, a
variety of observational studies have even suggested that
diuretics could actually be detrimental in heart failure,
further confusing the picture of how best to use these agents.
This review will primarily focus on loop diuretics—from
their mechanism of action and pharmacology to the avail-
able data addressing their role in heart failure therapy.
Mechanism of action and pharmacology of loop
diuretics
Loop diuretics inhibit the Na?/2Cl-/K? cotransporter of
the thick ascending loop of Henle, resulting in decreased
123

sodium and chloride reabsorbtion from the urine and
subsequent natriuresis and diuresis (Fig. 1). Other available
classes of diuretics such as thiazide-like diuretics (such as
thiazides and metolazone) and potassium sparing diuretics
(such as spironolactone) exert their effects on other parts of
the nephron. In general, these other classes of diuretics are
not sufficiently potent to be used as mono-therapy in
patients with symptomatic heart failure, although they may
be employed with loop diuretics as a strategy of
‘‘sequential nephron blockade’’ as described below. In
addition to their diuretic effects, loop diuretics may also
have other effects such as inducing the synthesis of pros-
taglandins, with subsequent renal and peripheral vascular
smooth muscle relaxation and vasodilatation. Diuretic
therapy is known to activate the renin–angiotensin–aldo-
sterone axis and the sympathetic nervous system, both of
which are known to have adverse effects in heart failure
[6, 7].
Understanding of the pharmacology of loop diuretics is
critical for optimizing their role in the treatment of heart
failure. Loop diuretics must be filtered at the glomerulus
and then reach a therapeutic concentration at the site of
action (in the tubule at the loop of Henle) in order to
achieve a pharmacodynamic effect. Because of this, con-
ditions that decrease glomerular filtration (such as renal
insufficiency or heart failure) shift the dose–response curve
for loop diuretics downward and the right, necessitating a
higher starting dose in order to achieve the same level of
diuresis (Fig. 2) [8]. Giving a dose that is insufficient to
reach a therapeutic concentration in the tubules is a com-
mon cause of an observed lack or response to diuretics in
patients with heart failure. Additionally, all currently
available loop diuretics are relatively short-acting drugs.
After dosing, the concentration in the tubular fluid declines
Fig. 1 Mechanism of action of different classes of diuretic at the
level of the nephron
123
Heart Fail Rev
Fig. 2 Dose–response curve of loop diuretics in heart failure patients
compared with normals. In heart failure patients, higher doses are
required to achieve a given diuretic effect and the maximal effect is
blunted. Adapted from Ellison [8]
below a therapeutic level, resulting in a period of ‘‘post-
diuretic sodium retention’’ [8]. With once daily dosing, this
period of sodium retention may actually overcome the
period of natriuresis, especially if dietary sodium intake is
not restricted. These pharmacodynamic considerations
explain why loop diuretics are generally more effective
when given in several divided doses as opposed to a single
daily dose.
Loop diuretics in the outpatient management
of heart failure
Despite uncertainty about optimal use of loop diuretics,
they remain a mainstay of heart failure therapy, and most
patients with symptomatic heart failure will require regular
doses of loop diuretics to maintain a euvolemic state.
Current guidelines recommend using the minimum dose of
loop diuretic required to maintain the patient free of signs
and symptoms of congestion [4]. This may require a pro-
cess of frequent reappraisal of diuretic requirements in the
face of changes in dietary sodium intake, fluid restriction,
concomitant medications, or disease status. In particular,
adherence to sodium restriction and avoidance of non-
steroidal anti-inflammatory drugs (based on the fact that
these drugs inhibit prostaglandin synthesis) are critical to
successful diuretic therapy, and direct questioning about
each of these should be an initial part of the evaluation of
the patient with decreased diuretic responsiveness or
worsening congestion.
The three commonly available loop diuretics (furose-
mide, torsemide, and bumetanide) all work via the same
mechanism in the loop of Henle, although there may be
clinically important differences in the pharmacology of
Heart Fail Rev
these agents. Although once daily use of furosemide is
convenient for patients, it is not optimal from a pharma-
codynamic perspective as described earlier, since daily
dosing results in a long period of sodium avidity by the
kidney when therapeutic diuretic concentrations are not
present. More frequent oral furosemide dosing serves to
limit this ‘‘rebound’’ effect. Although furosemide is by far
the most common oral loop diuretic, patients proving
resistant to oral furosemide therapy may benefit from a trial
of the second generation oral loop diuretics (bumetanide
and torsemide), which may offer greater efficacy due to
increased oral bioavailability and potency. In particular, the
longer half-life of torsemide may limit the rebound phe-
nomenon. Additionally, torsemide is more rapidly and
completely orally absorbed than is furosemide in patients
with heart failure [9]. An intriguing open label randomized
trial of furosemide versus torsemide in 234 patients
ambulatory heart failure patients suggested that torsemide
may reduce hospitalizations compared with furosemide,
although these data have not yet been replicated in more
carefully controlled studies [10]. All the available loop
diuretics share similar toxicity, including the possibility of
ototoxicity in high doses. Although it is seldom used in
current practice, ethacrynic acid may still be helpful in
patients with severe sulfa allergy since it is the only loop
diuretic that does not contain sulfa. Careful monitoring and
supplementation of electrolytes, particularly potassium, is a
crucial aspect of all loop diuretic therapy.
Diuretics in hospitalized heart failure patients
Most hospitalizations for acute decompensated heart fail-
ure are related to congestion, and loop diuretic therapy
remains the primary treatment for most patients hospital-
ized with heart failure. Over 90% of patients hospitalized
for heart failure are given loop diuretics, and the majority
of these are treated with loop diuretics alone [11].
Although escalating doses of oral diuretics may be used in
some selected circumstances, in general, intravenous loop
diuretic therapy works more quickly and eliminates
uncertainty about gastrointestinal absorption. Because oral
absorption may be less rapid in patients with heart failure
than in healthy populations, oral dosing may not reach
sufficient levels to achieve a diuretic effect in patients with
heart failure (Fig. 3). This may explain the frequent clinical
observation that patients experience progressively dimin-
ishing diuretic efficacy of outpatient diuretics in the days
leading up to a clinical decompensation. Administration of
intravenous furosemide to patients with heart failure and
congestion typically results in a prompt diuretic effect
(within 30 min) that peaks at 1.5 h. For most patients, this
diuresis is accompanied by a decrease in ventricular filling
Fig. 3 Comparison of pharmacokinetics of oral and intravenous loop
diuretics. While oral dosing may achieve diuretic concentrations
sufficient to cause diuresis in normals, it may not reach the higher
concentrations required to achieve diuresis in heart failure patients.
This explains the need for higher doses of oral diuretics or the use of
intravenous diuretics in patients with heart failure. Adapted from
Ellison [8]
pressures and improvement in symptoms. Intravenous loop
diuretics should generally be continued until euvolemia is
achieved, at which time patients can be transitioned back to
oral diuretic regimens. Monitoring of patients for 24 h on
oral diuretic therapy to ensure that volume retention does
not recur may prevent short-term rehospitalizations.
Challenges of diuretic therapy in heart failure:
diuretic resistance
Although most patients with symptomatic heart failure
respond to appropriate doses of diuretics, resistance to
diuretics is a common clinical problem in the management
of heart failure. Several mechanisms may contribute to this
progressive diminution of loop diuretic efficacy over time.
The ‘‘braking phenomenon’’ results from hemodynamic
changes at the glomerulus as well as from adaptive changes
in the distal nephron and may partially be mediated by
stimulation of the renin–angiotensin and sympathetic ner-
vous systems [12]. Persistent delivery of sodium to the
distal nephron causes hypertrophy of distal convoluted
tubule cells [13]. This change eventually leads to increased
sodium reabsorbtion and thereby negates the proximal
natriuretic effect exerted by the loop diuretic. This phe-
nomenon may be more pronounced in patients with
impaired renal function.
For patients who are continue to have poor response to
diuretics despite escalating doses, options include the use
of continuous infusion rather than intermittent boluses or
123

the addition of a thiazide or ‘‘thiazide-like’’ diuretic such as
metolazone. From a pharmacokinetic and pharmacody-
namic perspective, there are potential benefits of continu-
ous infusion as compared with intermittent bolus dosing.
Continuous infusion results in a more constant delivery of
diuretic to the tubule, potentially reducing the rebound
phenomenon described earlier and maintaining more con-
sistent diuresis. Additionally, continuous infusion is asso-
ciated with lower peak plasma concentrations, which may
be associated with a lower incidence of other side effects
such as ototoxicity, especially at higher doses. A meta-
analysis of multiple small studies reported continuous
infusion was associated with improved outcomes compared
with intermittent bolus dosing [14]. The most definitive
evaluation of the comparative efficacy of continuous
infusion compared with bolus dosing is the recent Diuretic
Optimization Strategies Evaluation (DOSE) study, descri-
bed in more detail below [15].
The addition of a thiazide or thiazide-like diuretic
(metolazone) as part of a strategy of sequential nephron
blockade is a common approach to diuretic resistance. The
available data on the use of thiazide-like diuretics as an
adjunct to loop diuretics have recently been reviewed in
detail [16]. Thiazides are typically given as a single oral
dose 1 h prior to loop diuretics. Although this strategy can
often be effective in overcoming diuretic resistance, careful
monitoring of fluid status and serum electrolytes such as
sodium, potassium, and magnesium is critical, since the
combination of metolazone and loop diuretics can induce
severe volume depletion or electrolyte disturbances. In
general, the chronic use of daily adjunctive metolazone
should be discouraged.
Aldosterone plays a critical role in cardiovascular
physiology. Excess circulating aldosterone has been well
described in heart failure and contributes to progressive
ventricular remodeling in part by accelerating turnover of
extracellular matrix [17]. Aldosterone antagonism with
either spironolactone or eplerenone is now well established
as a therapy for chronic heart failure and post-MI LV
dysfunction, based on the RALES [18], EMPHASIS [19],
and EPHESUS studies [20]. Although these agents are
technically diuretics, they generally have little diuretic
effect in patients with chronic heart failure in typically
used doses [18]. Much higher doses of spironolactone, up
to 400 mg daily, have been used in the treatment of
patients with cirrhosis, and small studies suggest that high
doses of aldosterone antagonists may be a useful adjunct to
loop diuretics in achieving natriuresis in diuretic-resistant
heart failure patients [21]. Given that relatively limited
safety data are available with this approach and the con-
cerns about the potential for hyperkalemia, such a strategy
should only be undertaken with great care and careful
monitoring of electrolytes and volume status.
123
Heart Fail Rev
Diuretics and outcomes
Despite their effectiveness in treating congestion, diuretics
may be associated with neurohormonal activation, wors-
ening renal insufficiency, electrolyte abnormalities, and
arrhythmias, raising concerns about the safety profile of
these drugs [22]. Although large placebo-controlled studies
of diuretics in human with symptomatic heart failure are
not feasible due to the need to actively manage symptoms
of congestion, an animal study using a porcine heart failure
model showed that treatment with furosemide resulted in
an increased progression of left ventricular systolic dys-
function [23]. In contrast, a meta-analysis of a heteroge-
neous group of small placebo-controlled studies has
suggested a mortality benefit of diuretic therapy in heart
failure [24]. A variety of observational studies have shown
a link between higher doses of diuretics and worsened
clinical outcomes [25–28]. These types of observations are
all confounded by the fact that patients receiving higher
doses of diuretics do so due to greater disease severity or
greater comorbidity (e.g., worse renal function), making it
impossible to establish whether the relationship between
diuretic dose and outcomes is causal. In particular, the
association of higher diuretic dosing with worsening renal
function during hospitalization has been cited as cause for
concern, since worsening renal function during ADHF
treatment has been frequently shown to be a predictor of
poor outcomes [29]. More recent data from several studies,
however, have suggested that transient worsening renal
function during acute heart failure therapy may not impact
post-discharge outcomes [30, 31]. Given that persistent
congestion is itself a predictor of both worsening renal
function [32] and adverse outcomes [33], it would appear
that transient worsening of renal function may be a rea-
sonable trade-off in exchange for better decongestion in
ADHF patients. Understanding the optimal balance
between the benefits of decongestion and the potential
adverse effects of therapies targeting congestion remains
an important area of research.
Data from the DOSE study
The DOSE study was the first robust multicenter random-
ized trial to compare the safety and efficacy of various
diuretic strategies in patients with acute decompensated
heart failure [15, 22]. DOSE-randomized 308 patients in a
2 9 2 factorial randomization to either high- or lose dose
(defined as either 2.5 or 1 times their chronic oral dose of
furosemide given IV) and again to either every 12-h
boluses or continuous infusion [15]. The coprimary end
points were improvement of global symptoms (as measured
by the area under the curve of serial assessments using a
Heart Fail Rev
visual analog scale (VAS AUC) and changes in creatinine
at 72 h. For bolus versus continuous infusion, there was no
difference in patient global assessment of symptoms (mean
AUC 4236 vs. 4373, P = 0.47) or in the mean change in
creatinine (0.05 mg/dL vs. 0.07 mg/dL, P = 0.45). For
high-dose versus low-dose, there was a trend toward
greater improvement in patient global assessment of
symptoms (mean AUC 4430 ± 1401 vs. 4171 ± 1436,
P = 0.06) and no significant difference in the mean change
in creatinine (0.08 vs. 0.04 mg/dL, P = 0.21). The high-
dose strategy was associated with greater efficacy in a
variety of secondary end points, including dyspnea, net
diuresis, and weight loss. There was a transient worsening
in renal function with high-dose diuretics, but this disap-
peared by the time of discharge. Although the study was
not powered to detect differences in clinical outcomes, the
incidence of the 60-day outcome of death, rehospitaliza-
tion, or emergency department visit was lower in the high-
dose than the low-dose arm (hazard ratio = 0.83, P =
0.28). Taken as a whole, the results of DOSE suggest that
higher doses of diuretics are likely to be more efficacious in
relieving congestion than a low-dose strategy, at the costs
of a small worsening of renal function that does not appear
to have long-term consequences in terms of outcomes.
These data suggest that prior studies demonstrating higher
mortality with higher doses of diuretics are unlikely to
represent a true cause and effect, but rather higher doses of
diuretics are markers for greater severity of illness. Recent
data suggest that transient renal worsening of renal func-
tion is not associated with long-term harm, providing fur-
ther support for the DOSE results [30]. Finally, data from
the ESCAPE study suggest that successful decongestion, as
quantified by laboratory evidence of hemoconcentration, is
critical to prevent rehospitalization in patients with
advanced heart failure [31].
Alternatives to loop diuretics
Given the limitations of traditional diuretics in heart fail-
ure, there has been substantial interest in developing
alternative strategies to manage congestion and volume
retention in heart failure patients. Vasopressin antagonists
block the effects of vasopressin at the distal convoluted
tubule and collecting duct, leading to an increase in free
water excretion, but have not been shown to improve post-
discharge outcomes in a large, randomized, controlled trial
of patients with ADHF [34, 35]. Adenosine receptor
antagonists appeared to be promising adjuncts to diuretic
therapy, but were not shown to be efficacious in ADHF in
the recently published PROTECT study [36]. Ultrafiltration
represents a novel mechanical approach to volume man-
agement in ADHF and appeared to have some benefits over
diuretics in the UNLOAD study [37]. Several ongoing
studies of ultrafiltration in heart failure will further define
the role of this technology in heart failure management.
Conclusions
Loop diuretic therapy plays a central role in the treatment
of heart failure. Although many unanswered questions
remain about the best approach for using diuretics in heart
failure, their demonstrated efficacy at relieving congestion
and the long clinical experience with these agents suggest
that they will remain an important part of the heart failure
armamentarium for the foreseeable future. The results of
DOSE suggest that some prior concerns about the safety of
high-dose diuretics may not be valid. Ongoing investiga-
tion into the optimal strategies to maintain the efficacy of
diuretics and minimize their adverse effects will continue
to improve our understanding of these agents.
Conflict of interest No conflict of interest with regard to the con-
tents of this manuscript.
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